CN1069728A - Maillard reaction inhibitor - Google Patents
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- CN1069728A CN1069728A CN92110177A CN92110177A CN1069728A CN 1069728 A CN1069728 A CN 1069728A CN 92110177 A CN92110177 A CN 92110177A CN 92110177 A CN92110177 A CN 92110177A CN 1069728 A CN1069728 A CN 1069728A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/54—Nitrogen and either oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
A kind of new Maillard reaction inhibitor that contains the compound or its salt of at least a formula (1) expression is disclosed; The method of preparation formula (1) compound or its salt; Suppress the in vivo composition of Maillard reaction, it comprises at least a formula (1) compound or its salt; And a kind of inhibition method of Maillard reaction in vivo, promptly impose formula (1 ') compound or its salt.
Description
The present invention relates to the new inhibitor of Maillard reaction.
Maillard reaction is a kind of like this reaction, that is: the attack to the aldehyde radical of reducing sugar (as glucose) that starts from vivo that nucleophilic reaction because of the free amino group that exists in the protein causes forms the Schiff's base that is called aldimine, then, aldimine can be rearranged into more stable Amadori compound (carbohydrate of non-enzymatic catalysis turns usefulness (glycation) into) successively.The Amadori compound further causes the reaction of the amino in a series of and other protein, thereby has formed the brown fluorescence thing and made between the protein crosslinked.In history, Mei Lade has reported that in 1912 the mixing solutions heating of amino acid and reducing sugar the time becomes brown (L.C.Maillard, Compt.Rend.Soc.Biol., 72,599(1912)), and since then, this reaction just is called Maillard reaction.Mei Lade hints at that time, and this reaction may in vivo take place.
Nineteen sixty-eight, people such as Rabber find hemoglobin A in diabetic subject's blood
1C(in the oxyphorase very little part) improved [S.Rabber et al., Clin.Chim.Acta.22,296(1968)]; Also find, reset form with Anadori, glucose is attached on the N-end Xie Ansuan of oxyphorase beta chain, has just formed hemoglobin A
1C(V.J.Stevens, H.Vlassara, A.Abati﹠amp; A.Cerami, J.Biol.Chem., 252,2998(1977)) or the like; And the carbohydrate that has proved the non-enzymatic catalysis in the live body turns the existence of usefulness into.
Recently, confirmed that various bioproteins can carry out Maillard reaction.For example, it is reported that the hemoglobin content that carries out carbohydrateization in the diabetic subject improves 3 times [E.C.Abraham et al., J.Lab.Clin.Med., 102,187(1983)].
Also have, it is reported, in diabetic subject's serum albumin, improved the amount that carbohydrate turns usefulness into (R.Dolhofer and O.H.Wieland, Diabetes, 29,417(1980)).And it is reported that fluorescence has improved (Vincent M.Monnier et al., Proc.Natl.Acad.Sci.U.S.A., 81,583(1984)) the skin glue source of collecting from the diabetic subject.
The carbohydrate of non-enzymatic catalysis turn into be a kind of in healthy people observed existing picture, and accumulation brown fluorescence material relates to and has the protein that postpones metabolic rate, this accumulation is now as the elderly with improved under the diabetic disease states of blood glucose value and obviously observed.People such as Patrick have reported to this reason, promptly determined the accumulation volume (J.S.Patrick of maillard reaction product by metabolic rate of blood glucose value, its target protein or the like, S.R.Thorpe and J.W.Baynes, Journal of Gerontology, 45,1, B18-23(1990)).
This maillard reaction product had been discussed in the past and about the relation between the various causes of disease of diabetes and human senescence.For example, it is reported, given mouse mainline after 12 weeks, caused the typical kidney dysfunction (B.A.McVerry et al., The Lancet, 5,738(1980)) of diabetes when the serum albumin that turns usefulness into through carbohydrate.Carbohydrate for the non-enzymatic catalysis of neurospongium phospholipoprotein matter turns into having participated in one of cause of disease of diabetics's nervous disorders, also done and study (V.M.Monnier et al., Clin.Endocrinol.Metab., 11,431(1982)).
The eyeball lens crystal is a kind ofly can not produce metabolic particular proteins after biosynthesizing, and people such as Cerami find that this crystal turns coloured cross-linking compounds (V.M.Monnier﹠amp that the time spent has formed the cross-linking compounds with disulfide key and had fluorescence into through carbohydrate; A.Cerami, Science, 211,491(1981) and V.M.Monnier﹠amp; A.Cerami, Biochim.Biophys.Acta., 760,97(1983)).Turn the time spent into when this crystal carries out carbohydrate, polymerization and non-solvency action have improved fluorescence and brown tint permanence, are similar to very much eyeball with the variation at age (S.H.Chiou et al., J.Biol.Chem., 256,5176(9181)).
The proteinic collagen and the elastin that constitute conjunctive tissue are the protein that demonstrates very low metabolic rate, glomerular basement membrane, skin, tendon, or the like in had been found that glucose is in conjunction with product (V.M.Monnier et al., " Maillard Reaction in Food ", Prog.Food Nutr.Sci., 5,315, Pergamon Press, London).
People such as Brownlee show that in the mouse that suffers from diabetes, the collagen cross-linking in the vessel wall has improved, thereby accumulated fluorescent substance, and thisly crosslinkedly finished (M.Brownlee et al., Science by non-enzymatic catalysis mechanism, 232,1629(1989)).Someone has also considered and arterial wall hardened relation (H.Rosenburn et al., Biochem.Biophys, Res, Commun., 91,498(1979)).
As mentioned above, can think that intravital Maillard reaction has participated in various and diabetes and human senescence diseases associated.
An object of the present invention is to provide a kind of new Maillard reaction inhibitor.
Another object of the present invention provides the method for preparation formula (1) compound and salt thereof.
Another purpose of the present invention provides the in vivo composition of Maillard reaction of a kind of inhibition, and it comprises at least a formula (1) compound or its salt.
A further object of the present invention provides the in vivo method of Maillard reaction of a kind of inhibition, promptly takes formula (1 ') compound or its salt.
That is to say, the invention provides a kind of Maillard reaction inhibitor, the compound or its salt that this inhibitor contains at least a following formula (1 ') expression is as activeconstituents:
R wherein
1Represent the phenoxy group low-grade alkane acidyl that can have lower alkoxycarbonyl on hydrogen atom, low alkyl group, carboxyl low-grade alkyl, lower alkoxycarbonyl low alkyl group, the phenyl ring, or low-grade cycloalkyl; R
2Representative-NHR
4(R wherein
4Represent hydrogen atom; Can have 1-3 substituent phenyl sulfonyl on the phenyl ring, described substituting group is selected from halogen atom, nitro, lower alkoxy and low alkyl group; The phenyl low-grade alkane acidyl or-CO-NHR
5, R wherein
5Represent phenyl, the phenyl lower alkyl that can have halogen atom on low alkyl group, the phenyl ring, or naphthyl) or-N=R
6(R wherein
6Represent low-grade alkylidene, the low-grade alkylidene that has 1 or 2 low-grade cycloalkyl, can have 1-3 substituent phenyl low-grade alkylidene on the phenyl ring, described substituting group is selected from halogen atom, carboxyl, lower alkoxycarbonyl, nitro, hydroxyl, lower alkoxy and junior alkyl halides, the phenyl lower alkenylene that can have nitro on the phenyl ring, lower alkenylene can have the phenoxy group low-grade alkylidene of carboxyl on rudimentary ring alkylidene group or the phenyl ring); R
3Represent two hydrogen atoms, can have the phenyl low-grade alkylidene of halogen atom or junior alkyl halides on the phenyl ring, or the phenyl lower alkenylene; And X representative-S-or-N(R
7)-(be R wherein
7Represent hydrogen atom, low alkyl group, carboxyl low-grade alkyl or lower alkoxycarbonyl low alkyl group); In addition, R
1And R
4, or R
4And R
7Can mutually combine and form the oxygen ethylidene.
Formula of the present invention (1 ') compound and salt thereof can be used for treatment or prevent various diabetic complications by suppressing Maillard reaction, for example coronary disease, circulatory disorder, cerebrovascular disorder, diabetes nerve functional disease, nephropathy, arteriosclerosis, arthrosclerosis, cataract and the retinitis or because the disease that causes of human senescence, as arteriosclerosis, senile cataract or the like.
Accompanying drawing shows the urinary albumin excretory result (mg/24 hour) of six trial periods in week that obtain according to pharmacological testing 2.
Below introduce in detail and be used for each group of the present invention.
No matter low alkyl group is individualism or is present in other group that its example has the C of straight or branched1-C
6Alkyl, for example methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, amyl group, hexyl, etc.
No matter lower alkoxy is individualism or is present in other group that its example has the C of straight or branched1-C
6Alkoxyl, for example methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy, amoxy, own oxygen base, etc.
No matter halogen atom is individualism or is present in other group, mean fluorine, chlorine, bromine and iodine.
The example of carboxyl low-grade alkyl has wherein, and moieties is the C of straight or branched1-C
6The carboxyalkyl of alkyl, for example carboxyl methyl, 2-carboxy ethyl, 1-carboxy ethyl, 3-carboxyl propyl group, 4-carboxybutyl, 1,1-dimethyl-2-carboxy ethyl, 5-carboxy pentyl, 6-carboxyl hexyl, 2-methyl-3-carboxyl propyl group, etc.
The example of lower alkoxycarbonyl low alkyl group has alkoxyl wherein partly to have the alkoxycarbonyl alkyl that 1-6 carbon atom and moieties have 1-6 carbon atom, such as methoxycarbonyl methyl, ethoxy carbonyl methyl, 3-methoxycarbonyl propyl group, 4-ethoxy carbonyl butyl, 6-propoxycarbonyl hexyl, 5-isopropoxy carbonyl amyl group, 1,1-dimethyl-2-butoxy carbonyl ethyl, 2-methyl-3-tertbutyloxycarbonyl propyl group, 2-penta oxygen carbonyl ethyl, own oxygen carbonyl methyl, etc.
The example of phenoxy group low-grade alkane acidyl has wherein, and alkanoyl moiety is straight or branched C2-C
6The phenoxy group alkanoyl of alkanoyl, for example 2-phenoxy group acetyl group, 3-phenoxy group propiono, 4-phenoxy group bytyry, 2-phenoxy group bytyry, 6-phenoxy group caproyl, 2-phenoxy group propiono, 3-phenoxy group bytyry, 4-phenoxy group-3-methylbutyryl base, 5-phenoxy group valeryl, 2-methyl-3-phenoxy group propiono etc.
There is the example of the phenoxy group low-grade alkane acidyl of a lower alkoxycarbonyl to comprise on the phenyl ring: the straight or branched C that a phenoxy group is arranged on the phenyl ring2-C
7Alkanoyl; the alkoxy carbonyl group of a straight or branched is arranged as substituting group (wherein alkoxyl partly has 1-6 carbon atom) on its phenyl; 2-(4-methoxycarbonyl group phenoxy group for example) acetyl group, 2-(3; 4-dimethoxycarbonyl phenoxy group) acetyl group, 2-(3; 4; 5-trimethoxy carbonyl phenoxy group) acetyl group, 2-(3-methoxycarbonyl group phenoxy group) acetyl group, 2-(2-methoxycarbonyl group phenoxy group) acetyl group, 3-(2-the third oxygen carbonyl phenoxy group) propiono, 4-(4-penta oxygen carbonyl phenoxy group) bytyry, 5-(3-the third oxygen carbonyl phenoxy group) valeryl, 6-(4-isobutyl boc phenoxy group) caproyl, the own oxygen carbonyl of 2-(4-phenoxy group) acetyl group; 2-(4-fourth phenoxy base) acetyl group, etc.
The example of low-grade cycloalkyl has C
3-C
8Low-grade cycloalkyl is as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group or the like.
The example of phenyl low-grade alkane acidyl has wherein, and alkanoyl moiety is the C of straight or branched
2-C
6The octadecyloxy phenyl acyl group of alkyloyl, for example phenyl acetyl, 3-phenyl propionyl, 4-phenyl butyryl radicals, 2,2-dimethyl-3-phenyl propionyl, 5-phenyl pentanoyl, 6-phenyl caproyl, 2-methyl-3-phenyl propionyl, or the like.
Can have example that 1-3 is selected from the phenyl sulfonyl of halogen atom, nitro, lower alkoxy and low-grade alkyl substituent on the phenyl ring has and can have 1-3 on the phenyl ring and be selected from halogen atom, nitro, straight or branched C
1-C
6Alkoxyl group and straight or branched C
1-C
6The phenyl sulfonyl of alkyl substituent; phenyl sulfonyl for example; 2-chloro-phenyl-alkylsulfonyl; 3-chloro-phenyl-alkylsulfonyl; 4-chloro-phenyl-alkylsulfonyl; 2-fluorophenyl alkylsulfonyl; 3-fluorophenyl alkylsulfonyl; 4-fluorophenyl alkylsulfonyl; 2-bromophenyl alkylsulfonyl; 3-bromophenyl alkylsulfonyl; 4-bromophenyl alkylsulfonyl; 2-iodophenyl alkylsulfonyl; 4-iodophenyl alkylsulfonyl; 3; 5-dichlorophenyl alkylsulfonyl; 2; 6-dichlorophenyl alkylsulfonyl; 3; 4-dichlorophenyl alkylsulfonyl; 3; 4-difluorophenyl alkylsulfonyl; 3; 5-dibromo phenyl alkylsulfonyl; 3; 4; 5-trichlorophenyl alkylsulfonyl; 2-aminomethyl phenyl alkylsulfonyl; 3-aminomethyl phenyl alkylsulfonyl; 4-aminomethyl phenyl alkylsulfonyl; 2-ethylphenyl alkylsulfonyl; 3-ethylphenyl alkylsulfonyl; 4-ethylphenyl alkylsulfonyl; 3-isopropyl phenyl alkylsulfonyl; 4-hexyl phenyl sulfonyl; 3; 4-3,5-dimethylphenyl alkylsulfonyl; 2; 5-3,5-dimethylphenyl alkylsulfonyl; 3; 4; 5-trimethylphenyl alkylsulfonyl; 2-p-methoxy-phenyl alkylsulfonyl; 3-p-methoxy-phenyl alkylsulfonyl; 4-p-methoxy-phenyl alkylsulfonyl; 2-ethoxyl phenenyl alkylsulfonyl; 3-ethoxyl phenenyl alkylsulfonyl; 4-ethoxyl phenenyl alkylsulfonyl; 4-isopropyl phenyl alkylsulfonyl; 4-hexyloxy phenyl sulfonyl; 3; 4-Dimethoxyphenyl alkylsulfonyl; 3; 4-diethoxy phenyl alkylsulfonyl; 3; 4; 5-trimethoxyphenyl alkylsulfonyl; 2; 5-Dimethoxyphenyl alkylsulfonyl; 2-nitrophenyl alkylsulfonyl; 3-nitrophenyl alkylsulfonyl; 4-nitrophenyl alkylsulfonyl; 2; 4-dinitrophenyl alkylsulfonyl; 3-methyl-4-chloro-phenyl-alkylsulfonyl; 2-chloro-6-aminomethyl phenyl alkylsulfonyl; 2-methoxyl group-3-chloro-phenyl-alkylsulfonyl, or the like.
Can have halogen atom on the phenyl ring and comprise the phenyl that can have 1-3 halogen atom as the example of substituent phenyl, for example phenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 4-iodophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromo phenyl, 3,4, the 5-trifluorophenyl, or the like.
The example of phenyl lower alkyl has wherein, and moieties is straight or branched C
1-C
6The phenylalkyl of alkyl, for example benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenyl propyl, 4-phenyl butyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenyl hexyl, 2-methyl-3-phenyl propyl, or the like.
The example of low-grade alkylidene has straight or branched C
1-C
6Alkylidene group, for example methylene radical, ethylidene, propylidene, isopropylidene, butylidene, the inferior tertiary butyl, pentylidene, hexylidene or the like.
The example that has the low-grade alkylidene of 1 or 2 low-grade cycloalkyl comprises and contains 1 or 2 C
3-C
8The straight or branched C of cycloalkyl
1-C
6Alkylidene group, for example 2-cyclopropyl ethylidene, 1-cyclobutyl ethylidene, 3-cyclopentyl propylidene, 4-cyclohexyl butylidene, 1,1-dimethyl-2-cyclohexyl ethylidene, 5-ring octyl group pentylidene, 6-cyclohexyl hexylidene, 2-methyl-3-cyclohexyl propylidene, two cyclopropyl methylene radical, 2-two cyclopropyl ethylidene, or the like.
The example of phenyl low-grade alkylidene has wherein, and alkylene moiety is straight or branched C
1-C
6The phenyl alkylidene group of alkylidene group, for example benzylidene, 2-benzyl ethylidene, 1-phenyl ethylidene, 3-phenyl propylidene, 4-phenyl butylidene, 1,1-dimethyl-2-phenyl ethylidene, 5-phenyl pentylidene, 6-phenyl hexylidene, 2-methyl-3-phenyl propylidene, or the like.
Can have 1-3 example that is selected from the substituent phenyl low-grade alkylidene of halogen atom, carboxyl, lower alkoxycarbonyl, nitro, hydroxyl, lower alkoxy and junior alkyl halides on the phenyl ring and comprise the straight or branched C that contains phenyl
1-C
6Alkylidene group on the wherein said phenyl ring, has 1-3 and is selected from following substituting group: the C of straight or branched
1-C
6The C of alkoxyl group, straight or branched
1-C
6Haloalkyl, halogen atom, carboxyl, the carbalkoxy that 1-6 carbon atom arranged on the alkoxyl group part, nitro and hydroxyl, 2-chlorine benzylidene for example, 4-fluorine benzylidene, the 2-(3-chloro-phenyl-) ethylidene, the 1-(4-chloro-phenyl-) ethylidene, the 3-(2-fluorophenyl) propylidene, the 4-(3-fluorophenyl) butylidene, 1,1-dimethyl-2-(4-fluorophenyl) ethylidene, the 5-(2-bromophenyl) pentylidene, the 6-(3-bromophenyl) hexylidene, 2-methyl-3-(4-bromophenyl) propylidene, 3-iodine benzylidene, the 2-(4-iodophenyl) ethylidene, 1-(3, the 5-dichlorophenyl) ethylidene, 2-(3, the 4-dichlorophenyl) ethylidene, 3-(2, the 6-dichlorophenyl) propylidene, 4-(3, the 4-dichlorophenyl) butylidene, 1,1-dimethyl-2-(3, the 4-difluorophenyl) ethylidene, 5-(3, the 5-dibromo phenyl) pentylidene, 6-(3,4, the 5-trichlorophenyl) hexylidene, 4-methyl fluoride benzylidene, 4-chloromethyl benzylidene, 4-brooethyl benzylidene, 4-iodomethyl benzylidene, 4-difluoromethyl benzylidene, 4-trifluoromethyl benzylidene, 4-trichloromethyl benzylidene, 2-(2-methyl fluoride phenyl) ethylidene, the 1-(3-chloromethyl phenyl) ethylidene, the 3-(3-2-bromomethylphenyl) propylidene, the 4-[4-(2-fluoro ethyl) phenyl] butylidene, the 5-[4-(2-chloroethyl) phenyl] propylidene, the 6-[3-(3-chloropropyl) phenyl] hexylidene, 2-methyl-3-[3-(4-chlorine hexyl) phenyl] propylidene, 2-(3,4-difluoromethyl phenyl) ethylidene, 2-(2, the 5-2-bromomethylphenyl) ethylidene, 2-(3,4, the 5-trifluoromethyl) ethylidene, 4-methoxyl group benzylidene, 3, the 4-dimethoxybenzylidenegroup group, 3,4,5-trimethoxy benzylidene, the 1-(3-p-methoxy-phenyl) ethylidene, the 2-(2-p-methoxy-phenyl) ethylidene, the 3-(2-ethoxyl phenenyl) propylidene, the 4-(4-ethoxyl phenenyl) butylidene, the 5-(3-ethoxyl phenenyl) benzylidene, the 6-(4-isopropyl phenyl) hexylidene, 4-butoxy benzylidene, 1,1-dimethyl-2-(4-hexyloxy phenyl) ethylidene, 2-methyl-3-(3, the 4-Dimethoxyphenyl) third subunit, 2-(3, the 4-Dimethoxyphenyl) ethylidene, 2-(3,4-diethoxy phenyl) ethylidene, 2-(3,4, the 5-trimethoxyphenyl) ethylidene, 1-(2, the 5-Dimethoxyphenyl) ethylidene, 2-carboxyl benzylidene, 3-carboxyl benzylidene, 4-carboxyl benzylidene, the 1-(2-carboxyl phenyl) ethylidene, the 2-(4-carboxyl phenyl) ethylidene, 3-(2,4-dicarboxyl phenyl) propylidene, the 4-(3-carboxyl phenyl) butylidene, the 5-(2-carboxyl phenyl) pentylidene, the 6-(3-carboxyl phenyl) hexylidene, 2-nitro benzylidene, 3-nitro benzylidene, 4-nitro benzylidene, 3,4,5-trinitro-benzylidene, the 1-(2-nitrophenyl) ethylidene, the 2-(4-nitrophenyl) ethylidene, 3-(2, the 4-dinitrophenyl) propylidene, the 4-(3-nitrophenyl) butylidene, the 5-(3-nitrophenyl) pentylidene, the 6-(3-nitrophenyl) hexylidene, 2-methoxyl group-3-chlorine benzylidene, 2-hydroxyl benzylidene, 2-(3, the 4-dihydroxy phenyl) ethylidene, 1-(3, the 4-dihydroxy phenyl) ethylidene, the 2-(3-hydroxy phenyl) ethylidene, the 3-(4-hydroxy phenyl) propylidene, 6-(3, the 4-hydroxy phenyl) hexylidene, 2,4-dihydroxyl benzylidene, 3,4,5-trihydroxy-benzylidene, 4-methoxycarbonyl benzylidene, 3,4-dimethoxy carbonyl benzylidene, 3-(2-ethoxy carbonyl phenyl) benzylidene, the different third oxygen carbonyl phenyl of 6-(4-) hexylidene, 4-butoxy carbonyl benzylidene, the own oxygen carbonyl of 4-benzylidene, or the like.
The example that can have the phenyl lower alkenylene of nitro on the phenyl ring comprises that wherein alkenylene partly is straight or branched C
2-C
6The phenyl alkenylene that can have 1-3 nitro on alkenylene and the phenyl ring, for example phenyl vinylidene, 4-nitrophenyl vinylidene, 3-phenyl acrol, 3-(4-nitro) phenyl acrol, 4-phenyl-2-crotonylidene, 4-phenyl-3-crotonylidene, 1-methyl-3-phenyl acrol, 2-methyl-3-phenyl acrol, 5-phenyl-2-inferior pentenyl, the inferior hexenyl of 6-phenyl-2-, or the like.
The example of lower alkenylene has the C of straight or branched
2-C
6Alkenylene, the inferior hexenyl of vinylidene, acrol, 2-crotonylidene, 3-crotonylidene, 2-inferior pentenyl, 2-for example, or the like.
The example of rudimentary ring alkenylene has C
3-C
8The ring alkenylene, for example 2-ring propenylidene, 2-ring crotonylidene, 2-ring inferior pentenyl, 2-cycloethylene thiazolinyl, 2-encircle inferior heptenyl, 2-encircles inferior octenyl, or the like.
The example that can have the phenoxy group low-grade alkylidene of carboxyl on the phenyl ring has the phenoxy group alkylidene group that can have carboxyl on the phenyl ring, and wherein alkylene moiety is the C of straight or branched
1-C
6Alkylidene group, phenoxy group methylene radical for example, 2-phenoxy group ethylidene, 1-phenoxy group ethylidene, 3-phenoxy group propylidene, 4-phenoxy group butylidene, 1,1-dimethyl-2-phenoxy group ethylidene, 5-phenoxy group pentylidene, 6-phenoxy group hexylidene, 2-methyl-3-phenoxy group propylidene, 2-carboxyl phenoxy group methylene radical, 1-(3-carboxyl phenoxy group) ethylidene, 2-(4-carboxyl phenoxy group) ethylidene, 3-(2-carboxyl phenoxy group) propylidene, 4-(3-carboxyl phenoxy group) butylidene, 1,1-dimethyl-2-(4-carboxyl phenoxy group) ethylidene, 5-(2-carboxyl phenoxy group) pentylidene, 6-(3-carboxyl phenoxy group) hexylidene, 2-methyl-3-(4-carboxyl phenoxy group) propylidene, or the like.
Can have the example that is selected from halogen atom and the substituent phenyl low-grade alkylidene of junior alkyl halides on the phenyl ring and comprise that those contain straight or branched C
1-C
6The phenyl alkylidene group of alkylene moiety wherein can have 1-3 and be selected from halogen atom and straight or branched C on the phenyl ring
1-C
6The substituting group of haloalkyl, benzylidene for example, 2-phenyl ethylidene, 1-phenyl ethylidene, 3-phenyl phenylene, 4-phenyl butylidene, 1,1-dimethyl-2-phenyl ethylidene, 5-phenyl pentylidene, 6-phenyl hexylidene, 2-methyl-3-phenyl propylidene, 4-fluorine benzylidene, 4-chlorine benzylidene, 4-bromine benzylidene, 4-iodine benzylidene, the 2-(2-fluorophenyl) ethylidene, the 1-(3-chloro-phenyl-) ethylidene, the 3-(3-bromophenyl) propylidene, 4-methyl fluoride benzylidene, 4-chloromethyl benzylidene, 4-brooethyl benzylidene, 4-iodomethyl benzylidene, 4-difluoromethyl benzylidene, 4-trifluoromethyl benzylidene, 4-trifluoromethyl benzylidene, 2-(2-methyl fluoride phenyl) ethylidene, the 1-(3-chloromethyl phenyl) ethylidene, the 3-(3-2-bromomethylphenyl) propylidene, the 4-[4-(2-fluoro ethyl) phenyl] butylidene, the 5-[4-(2-chloroethyl) phenyl] propylidene, the 6-[3-(3-chloropropyl) phenyl] hexylidene, 2-methyl-3-[3-(4-chlorine hexyl) phenyl] propylidene, 2-(3,4-difluoromethyl phenyl) ethylidene, 2-(2,5-xylylene bromide base) ethylidene, 2-(3,4,5-trichloromethyl phenyl) ethylidene, or the like.
R in formula of the present invention (1) compound
1When being hydrogen atom, this compound can have following isomer structure (1A)-(1C).
The present invention also comprises all these isomer and other steric isomer, optically active isomer and geometrical isomer in its scope.
Be used for formula of the present invention (1 ') compound and partly comprise known compound, but most compounds is new.
Formula of the present invention (1) compound can prepare by different methods, for example adopts the method shown in following reactions steps I-IX.
The reactions steps I
In following formula, R
1, R
2And R
7Define as above R
8Represent common ester residue.
By R
8The example of shown ester residue has C
1-C
6Low alkyl group and phenyl lower alkyl.
Above-mentioned being reflected in the suitable solvent carried out, and temperature of reaction is about room temperature-200 ℃, preferably about 60-100 ℃.
The solvent that is suitable for above-mentioned reaction is a lower alcohol, as methyl alcohol, ethanol or Virahol; Ether is as diox, tetrahydrofuran (THF) (THF), glycol dimethyl ether or ether; Aromatic hydrocarbons is as benzene, toluene or dimethylbenzene; Tertiary amine is as triethylamine or tripropyl amine; And polar solvent, as dimethyl formamide (DMF) or methyl-sulphoxide (DMSO).
The consumption of compound shown in the above-mentioned formula (3) suitable at least with formula (2) compound equimolar amount, the preferably 1-3 of formula (2) compound amount doubly (mole).
In general, complete at about 24 hours internal reactions of about 1-.
The reactions steps II
In the following formula, R
1, R
2And R
8Define as above, and Y represents halogen atom.
More than reaction is to use usual vehicle, carries out in the presence of reductor.
Suitable reductor comprises basic cpd, as salt of wormwood, yellow soda ash, sodium hydroxide, sodium bicarbonate, triethylamine, tripropyl amine, pyridine, quinoline, 4-dimethylaminopyridine and sodium acetate.
Concerning solvent, can use multiple common solvent, its example has lower alcohol, as methyl alcohol, ethanol or Virahol; Ether is as diox, tetrahydrofuran (THF) (THF), glycol dimethyl ether or ether; Aromatic hydrocarbons is as benzene, toluene or dimethylbenzene; Tertiary amine is as triethylamine or tripropyl amine; And polar solvent, as dimethyl formamide (DMF) or methyl-sulphoxide (DMSO).Temperature of reaction is preferably about room temperature-150 ℃, preferably about 50-100 ℃.
The consumption of compound shown in the above-mentioned formula (5) suitable at least with compound equimolar amount shown in the formula (4), preferably about 1-3 of latter's consumption times (mole).
The consumption of reductor is 1-10 doubly (mole), preferably about 1-3 times (mole) of compound amount shown in the formula (4).
General about 1-24 hour of reaction times.
The reactions steps III
In the following formula, R
1, R
6Define as above with X, A represents halogen atom.
Work as R
1When being low alkyl group, carboxyl low-grade alkyl, lower alkoxycarbonyl low alkyl group or low-grade cycloalkyl, reaction is to carry out with common substitution reaction in the presence of as catalyzer at alkali.
The example that is used for the suitable alkali of above reaction has salt of wormwood, yellow soda ash, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, triethylamine and tripropyl amine.
For solvent, can use multiple solvent commonly used, its example has lower alcohol, as methyl alcohol, ethanol or Virahol; Ether is as diox, tetrahydrofuran (THF) (THF), glycol dimethyl ether or ether; Aromatic hydrocarbons is as benzene, toluene or dimethylbenzene; Tertiary amine is as triethylamine or tripropyl amine; And polar solvent, as dimethyl formamide (DMF) or methyl-sulphoxide (DMSO).
Temperature of reaction is preferably about 0 ℃-100 ℃, generally about 1-20 hour of reaction times.
The ratio of formula (1c) compound and formula (6) compound is about 1-3 times (mole).
The consumption of alkali is the about 1-3 mole of every mole of formula (1c) compound.
In formula (1c), when X is-N(R
7) and R
7When being hydrogen atom,, for example be 2-5 times (mole) of formula (1c) compound amount, then by R if reaction is employing formula (a 6) compound high molar ratio
1And R
7(=R
1) shown in above group be incorporated into simultaneously under the condition of above-mentioned substitution reaction on 1-position and the 3-position.
Work as R
1Be in the time of can having the phenoxy group low-grade alkane acidyl of lower alkoxycarbonyl on phenyl ring, reaction is to form reaction (as the carboxylic acid halides method) according to traditional amido linkage to carry out.This carboxylic acid halides method is in suitable solvent, carries out in the presence of reductor.Reductor can be to be used for the various reductors that traditional amido linkage forms reaction, as sodium bicarbonate, yellow soda ash, salt of wormwood, pyridine or triethylamine.For solvent, can use solvent commonly used, as water, benzene, chloroform, trichloromethane, tetracol phenixin, diox or tetrahydrofuran (THF).
The ratio of compound shown in the formula (6) and formula (1c) compound generally at least about etc. mol ratio, about 1-3 of latter's consumption doubly (mole) preferably.Also have, the consumption of reductor is the about 1-3 mole of every mole of formula (1c) compound.Generally about-30 ℃-Yue 100 ℃ of temperature of reaction, preferably about room temperature-80 ℃, and within about 20 minutes-Yue 20 hours, react and finish.
The reactions steps IV
In the following formula IV, R
1Define as above R with X
6aRepresent low-grade alkylidene, and R
6bRepresent can have 1-3 on the phenyl ring and be selected from the substituent phenyl low-grade alkylidene of halogen atom, carboxyl, nitro, hydroxyl, lower alkoxy and junior alkyl halides, the phenyl lower alkenylene, or can have the phenoxy group low-grade alkylidene of carboxyl on the phenyl ring.
Above-mentioned reaction can be carried out in the presence of basic cpd or acidic cpd and in solvent.
Spendable solvent has acetate, benzene,toluene,xylene, methyl alcohol, ethanol, propyl alcohol, pyridine, picoline, DMF, DMSO or the like.
The basic cpd that can be used for above-mentioned reaction has sodium acetate, salt of wormwood, halo salt of wormwood, sodium alkoxide or the like; Spendable basic cpd has ammonium chloride, ammonium sulfate, the vitriol oil, or the like.
The common consumption of formula (7) compound at least with the about equimolar amount of formula (1d) compound, the about 1-2 mole of preferred every mole of formula (1d) compound.The consumption of basic cpd or acidic cpd also is the about 1-2 mole of every mole of formula (1d) compound.
Temperature of reaction about room temperature-150 ℃, preferably about 50-100 ℃, and finish at about 1-60 hour internal reaction.
The reactions steps V
In the following formula, R
1Define as above with X; R
2aRepresentative-N=R
6a,-N=R
6bOr-NHR
4a(R wherein
6bDefine as above R
6aRepresent low-grade alkylidene, and R
4aRepresentative can have 1-3 phenyl sulfonyl that is selected from halogen atom, nitro, lower alkoxy and low-grade alkyl substituent on phenyl ring); R
3aRepresent the phenyl low-grade alkylidene or the phenyl lower alkenylene that can have junior alkyl halides on the phenyl ring; R
2bRepresentative-N=R
3a,-N=R
6bOr-NHR
4a, R wherein
3a, R
6bAnd R
4aDefinition as above.
R in above-mentioned formula (1f)
2aBe-N=R
6aThe time, above-mentioned reaction generally is by reactions steps IV the same manner, every mole of formula (1f) compound uses at least about 2 moles, the preferred formula of about 2-3 mole (8) compound, thus the formula of obtaining (1g) compound (R wherein
2bFor-N=R
3a).
R in formula (1f)
2aBe-N=R
6bOr-NHR
4aThe time, reaction generally is the same manner by the reactions steps IV, use formula (8) compound carries out, its consumption at least with formula (1f) compound equimolar amount, about 1-2 times (mole) of latter's consumption preferably, thereby the formula of obtaining (1g) compound, wherein R
2bFor-N=R
6bOr-NHR
4a
The reactions steps VI
In the following formula, R
1, R
3, R
6Define as above with X.
In the presence of the organic or inorganic acidic cpd, carry out above reaction.Spendable organic or inorganic acidic cpd comprises hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetate, formic acid, or the like.Among these acidic cpds, particularly preferably be rare strong acid, example hydrochloric acid or sulfuric acid.
Spendable solvent comprises the stable conventional solvent of acid, as methyl alcohol, ethanol, diox, tetrahydrofuran (THF) or water.
The consumption of acidic cpd is about 1-20 times (mole) of formula (1d ') compound.
Reaction is usually about 60 minutes of about 30 ℃-Yue 120 ℃ of about 5-.
The reactions steps VII
In the following formula, R
1, R
3Define as above with X; R
9Representative can have 1-3 phenyl that is selected from halogen atom, nitro, lower alkoxy and low-grade alkyl substituent on phenyl ring; And B represents halogen atom.
In formula of the present invention (1) compound, R wherein
4Be on phenyl ring, can have 1-3 those compounds that are selected from the phenyl sulfonyl of halogen atom, nitro, lower alkoxy and low alkyl group can synthesize by common sulfonation reaction according to the reactions steps VII.
In the presence of alkali (as salt of wormwood), use the solvent of ether, diox, tetrahydrofuran (THF) or water or its mixture and so on to carry out above-mentioned reaction.
The consumption of formula (9) compound is the about 1-3 mole of every mole compound (1h).Reaction generally is about 24 hours of about 0 ℃-Yue 60 ℃ of about 1-.
The reactions steps VIII
In the following formula, R
3, R
6Define as above with X, and R
10Represent low alkyl group.
The reactions steps IX
In the following formula, R
1, R
3, R
6Define as above R with X
10Represent low alkyl group.
Reactions steps VIII and reactions steps IX are the reactions that forms the oxygen ethylidene, that is: at the 2-position of formula (1) (R in formula (1) compound
1And/or R
7When being the lower alkoxycarbonyl methyl) bonding lower alkoxycarbonyl methyl and=N-R
2
Above-mentioned cyclization can carry out according to the same manner of reactions steps VI.Reaction generally is about room temperature-Yue 150 ℃, preferably carried out about 5 minutes-Yue 60 minutes at about 30 ℃-Yue 120 ℃.
Also can carry out this reaction by vacuum-sublimation formula (1j) compound.
By the hydrolysis of common ester, wherein R
1Or R
7Formula (1) compound that is the lower alkoxycarbonyl low alkyl group can be transformed into the compound with corresponding carboxyl low-grade alkyl.
For above-mentioned reaction, can use multiple solvent commonly used, the example of solvent has methyl alcohol, ethanol, diox, tetrahydrofuran (THF), water or the like.
Reaction generally is about room temperature-Yue 120 ℃, preferably about room temperature-Yue 60 ℃ was carried out about 1 hour-Yue 24 hours.In the reaction, can use the alkali that is generally used for ester hydrolysis, its preferred example has sodium hydroxide, potassium hydroxide, or the like.
Some compounds as the formula (4) of the initiator of above-mentioned reactions steps II are preceding unknown compounds, and the preparation method of these initiators is as follows.
The reactions steps X
In the following formula, R
1And R
5Definition as above.
More than reaction is to carry out in the inert solvent such as ether, tetrahydrofuran (THF), diox, water or its mixture.The consumption of formula (11) compound is generally the about 1-3 mole of every mole of formula (10) compound.Reaction was normally carried out about 1 hour-Yue 20 hours at about 0 ℃-Yue 50 ℃.
In compound of the present invention, the compound of being represented by following formula (1) is new compound.
R wherein
1Represent hydrogen atom, low alkyl group, carboxyl low-grade alkyl, the lower alkoxycarbonyl low alkyl group can have the phenoxy group low-grade alkane acidyl or the low-grade cycloalkyl of lower alkoxycarbonyl on the phenyl ring; R
2Representative-NHR
4, R wherein
4Represent hydrogen atom, can have the phenyl sulfonyl that 1-3 is selected from halogen atom, nitro, lower alkoxy and low-grade alkyl substituent on the phenyl ring, the phenyl low-grade alkane acidyl or-CO-NHR
5(R wherein
5Represent low alkyl group, can have the phenyl of halogen atom on the phenyl ring, phenyl lower alkyl, or naphthyl), or-N=R
6(R wherein
6Represent low-grade alkylidene, low-grade alkylidene with 1 or 2 low-grade cycloalkyl, can have 1-3 on the phenyl ring and be selected from the substituent phenyl low-grade alkylidene of halogen atom, carboxyl, lower alkoxycarbonyl, nitro, hydroxyl, lower alkoxy and junior alkyl halides, the phenyl lower alkenylene that can have nitro on the phenyl ring, lower alkenylene, rudimentary ring alkylidene group, or can have the phenoxy group low-grade alkylidene of carboxyl on the phenyl ring); R
3Represent two hydrogen atoms, can have the phenyl low-grade alkylidene of halogen atom or junior alkyl halides on the phenyl ring, or the phenyl lower alkenylene; And X representative-S-or-N(R
7)-(be R wherein
7Represent hydrogen atom, low alkyl group, carboxyl low-grade alkyl or lower alkoxycarbonyl low alkyl group; R
1And R
4, or R
4And R
7Can be incorporated into the oxygen ethylidene, condition is to work as R
1Be hydrogen atom, R
3Be two hydrogen atoms and X be-during S-, R
2Be not-NHR
4(R wherein
4Be the phenyl sulfonyl that can have lower alkoxy on hydrogen atom or the phenyl ring) or-NH=R
6(R wherein
6Represent low-grade alkylidene, can have the phenyl low-grade alkylidene of halogen atom, nitro, hydroxyl or lower alkoxy on the phenyl ring, or can have the phenyl lower alkenylene of nitro on the phenyl ring); And work as R
1Be hydrogen atom, R
2Be-N=R
6And X is-S-or-during NH-, R
3And R
6Can not be the phenyl low-grade alkylidene simultaneously; Have again, work as R
2Be-NHR
4, R
3Be two hydrogen atoms and X be-during S-, R
1And R
4Be not incorporated into the oxygen ethylidene.
Compound of the present invention comprises the medicinal additive salt that forms with acid or basic cpd.
Make the reaction of acid as follows or alkali and compound of the present invention can easily form these salt.The example that is used to form the acid of salt has mineral acid, and example hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide or the like also can be organic acids, as oxalic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, phenylformic acid or the like.In addition, the example that is used to form the basic cpd of salt has sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash, saleratus, or the like.
Can from reactive system, easily separate with formula (1) compound and salt thereof that above-mentioned every kind of method makes, and with traditional separation means such as distillation method, recrystallization method, column chromatography, preparative thin-layer chromatography, solvent extration or the like purifying.
Maillard reaction inhibitor of the present invention generally is to use with common pharmaceutical dosage forms.The worker adopts thinner or excipient such as filler, expanding material, tackiness agent, wetting agent, disintegrating agent, tensio-active agent, lubricant or the like preparation preparation.
For pharmaceutical preparation, select different dosage form according to therapeutic purpose.Its typical example is tablet, pill, pulvis, liquid, suspensoid, emulsion, granula, capsule, suppository, injection (liquid, suspension, or the like), ointment, or the like.
For forming tablet, spendable carrier has excipient, as lactose, sucrose, sodium-chlor, glucose, urea, starch, lime carbonate, kaolin, crystalline cellulose, silicic acid or the like; Tackiness agent, as water, ethanol, propyl alcohol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methylcellulose gum, potassiumphosphate, Polyvinylpyrolidone (PVP), or the like; Disintegrating agent, as dry starch, sodiun alginate, agar-agar powder, laminated powder, sodium bicarbonate, lime carbonate, Vykamol Sorbitol 8B, Sodium Lauryl Sulphate BP/USP, stearic acid monoglyceryl ester, starch, lactose, or the like; The disintegration inhibitor, as sucrose, tristearin, theobroma oil, winterized stearin, or the like; Absorb accelerator, as quaternary ammonium hydroxide, Sodium Lauryl Sulphate BP/USP, or the like; Wetting Agent for Printing Inks, as glycerine, starch, or the like; Absorption agent, as starch, lactose, kaolin, wilkinite, colloid silicic acid, or the like; Lubricant, as talcum, stearate, boric acid powder, the polyoxyethylene glycol of purifying, or the like.In addition, need, tablet can be with common coating dressing to form for example sugar coated tablet, gel coat tablet, enteric coated tablets, film coated tablet, double-layer coatings tablet and multilayer tablet.
For forming pill, spendable carrier has vehicle, as sucrose, lactose, starch, theobroma oil, hardened vegetables oil, kaolin, talcum, or the like; Tackiness agent, as gummi arabicum pulveratum, tragacanth gum powder, gelatin, ethanol, or the like; Disintegrating agent is as laminated powder, agar-agar or the like.
For forming suppository, spendable carrier has polyoxyethylene glycol, theobroma oil, higher alcohols, high alcohol ester, gelatin, semi-synthetic glyceryl ester.
The preparation capsule is to adopt traditional method, that is: compound of the present invention is mixed with above-mentioned various carriers, and mixture pack into hard gelatine capsule, hard capsule or the like.
For the preparation injection, liquid, emulsion or suspension be through sterilization, and preferably make blood etc. is oozed.For the preparation injection, can make water, lactic acid aqueous solution, ethanol, propylene glycol, ethoxylation isooctadecanol, polyoxyethylene sorbitan fatty acid esters or the like as thinner.In this case,, can mix sodium-chlor, glucose or the glycerine of q.s in the pharmaceutical preparation, perhaps can add common solubility promoter, buffer reagent, subtract pain agent or the like for the preparation isotonic solution.In addition, if desired, can add tinting material, sanitas, spices, flavouring agent, sweeting agent or the like and other medicament in the pharmaceutical preparation.
For preparation paste, ointment and gel, can use white vaseline, paraffin, glycerine, derivatived cellulose, polyoxyethylene glycol, siloxanes, wilkinite or the like as thinner.
The amount of contained The compounds of this invention can be selected in wide range in the pharmaceutical preparation of the present invention, is not particularly limited, but generally accounts for the 1-70%(weight of pharmaceutical preparation).
Medication for pharmaceutical preparation of the present invention does not have particular restriction, according to patient's age, sex and other situation, symptom and dosage form selection different methods.Pharmaceutical preparation is mode whole body or the topical by oral or administered parenterally normally.
For example, the preparation compound is oral with tablet, pill, liquid, suspension, emulsion, granula or capsule form, or with the injection form administration, or as the mixture of other common auxiliary liq by intravenous injection, intramuscularly, intradermal injection, subcutaneous injection or peritoneal injection administration.
In other method, the form rectal administration that preparation can suppository, form that also can ointment is used.
The dosage of pharmaceutical preparation of the present invention can suitably be selected according to patient's age, body weight, disease time, curative effect, medication, treatment time or the like, but general dosed administration with every kg body weight about 0.1-100mg every day.
Can be with preparation once a day to administration several times.Certainly, dosage level changes with different condition.So under different situations, dosage can be lower than above-mentioned scope, also can be higher than above-mentioned scope.
Below, with the form of embodiment the preparation of the compound that the present invention uses and the pharmacological tests of these compounds are shown, give preparation example.
Embodiment 1
(1) add 4.00g isopropylidene aminoguanidine in the 1.61g sodium Metal 99.5 is dissolved in the methanol solution of the sodium methylate that 100ml methyl alcohol makes, after 1 hour, add the 5.88g glycine ethyl ester hydrochloride in the stirring at room mixture inward, reflux is 16 hours then.After the reaction mixture, add water and chloroform inward, again with water layer chloroform extraction three times so that mixture is distributed in water and the chloroform.
Organic layer and extraction liquid merge, after the anhydrous magnesium sulfate drying mixture, with the mixture concentrating under reduced pressure, resistates is contained in chromatography on the silicagel column, and with the mixed solvent of chloroform and methyl alcohol (100: 1, volume ratio) wash-out obtains 0.81g 2-isopropylidene hydrazono-imidazolidine-4-ketone white crystal.
NMR（CD
3OD）δppm：
3.93（s，2H）
1.99（d，J＝5.71Hz，6H）
m.p.182 to 187℃.
Similar approach according to above-mentioned steps (1) obtains following compound.
(2) 2-benzylidene hydrazono-imidazolidine-4-ketone
m.p.246-248℃
(3) 2-Alpha-Methyl cinnamylidene hydrazono-imidazolidine-4-ketone
m.p.243-245℃
(4) 2-ring pentylidene hydrazono-imidazolidine-4-ketone
NMR（DMSO-d
6）δ：
3.75（s，2H）
2.29-2.49（m，4H）
1.65-1.88（m，4H）
(5) imidazolidine-4-ketone 2-(1-cyclopropyl ethylidene hydrazono-)
m.p.169-172℃
NMR（DMSO-d
6）δ：
3.81（s，2H）
1.74（s，3H）
1.50-1.63（m，1H）
0.64-0.85（m，4H）
(6) 2-cyclohexylmethylene hydrazono-imidazolidine-4-ketone
NMR（DMSO-d
6）δ：
7.36（d，J＝5.61Hz，1H）
3.26（s，2H）
2.17-2.29（m，1H）
1.64-1.75（m，4H）
1.15-1.30（m，5H）
(7) 2-cyclohexylene hydrazine hydrazono-imidazolidine-4-ketone
NMR（DMSO-d
6）δ：
3.97（s，2H）
2.50-2.53（m，2H）
2.28-2.31（m，2H）
1.66-1.69（m，6H）
(8) the positive butylidene hydrazono-imidazolidine of 2--4-ketone
m.p.158-162℃
NMR（DMSO-d
6）δ：
7.47（t，J＝5.61Hz，1H）
3.76（s，2H）
2.16-2.29（m，2H）
1.41-1.57（m，2H）
0.90（t，J＝7.26Hz，3H）
(9) 2-two cyclopropyl methylene radical hydrazono-imidazolidine-4-ketone
NMR（DMSO-d
6）δ：
3.79（s，2H）
0.47-1.06（m，10H）
(10) imidazolidine-4-ketone 2-(1-trifluoromethyl ethylidene hydrazono-)
NMR（DMSO-d
6）δ：
11.28（s，1H）
7.79（s，1H）
3.98（s，2H）
2.06（s，3H）
(11) 2-hexafluoroisopropyli,ene hydrazono-imidazolidine-4-ketone
NMR（DMSO-d
6）δ：
3.99（s，2H）
(1) add 5.70g benzylidene aminoguanidine in the methanol solution that is dissolved in the sodium methylate that 150ml methyl alcohol makes by the 2.30g sodium Metal 99.5, after 1 hour, add the 11.35g diethyl iminodiacetate in the stirring at room mixture inward, reflux is 17 hours then.
After the reaction mixture, add water and chloroform in the mixture so that mixture is distributed between water and the chloroform.After reclaiming organic layer, water layer chloroform extraction three times.Organic layer and extraction liquid merge.After the anhydrous magnesium sulfate drying mixture, the concentrating under reduced pressure mixture, the resistates that forms is contained in chromatography on the silicagel column and with mixed solvent (100: the 1 volume ratios) wash-out of chloroform and methyl alcohol, obtains 2.61g 2-benzylidene hydrazono--1-methoxycarbonyl Methylimidazole alkane-4-ketone.
m.p.149-153℃
NMR（CDCl
3）δppm：
8.26（s，1H）
7.32-7.68（m，5H）
4.23（s，2H）
4.01（s，2H）
3.77（s，3H）
(2) add 40ml methyl alcohol and 14ml 2N sodium hydroxide solution in the 2.61g compound that makes toward above-mentioned step, and in stirring at room mixture 4 hours.The reaction mixture that concentrating under reduced pressure obtains.Add in resistates after the 10ml water, mixture neutralizes with 1N hydrochloric acid.Insolubles reclaims and water and ether wash-out with filtering method, obtains 1.82g 2-benzylidene hydrazono--1-carboxyl Methylimidazole alkane-4-ketone.
m.p.218-222℃
NMR（DMSO-d
6）δppm：
11.37（brs，1H）
8.16（s，1H）
7.34-7.86（m，5H）
4.08（s，2H）
4.02（s，2H）
By obtaining following compound with the above-mentioned steps similar approach.
(3) 2-isopropylidene hydrazono--1-methoxycarbonyl Methylimidazole alkane-4-ketone
NMR（CDCl
3）δppm：
4.15（s，2H）
4.02（s，2H）
3.76（s，3H）
1.97（s，3H）
1.94（s，3H）
(4) 1-methoxycarbonyl methyl-2-Alpha-Methyl cinnamylidene hydrazono-imidazolidine-4-ketone
NMR（CDCl
3）δppm：
8.40（s，1H）
7.26（s，5H）
6.72（s，1H）
4.22（s，2H）
4.09（s，2H）
3.78（s，3H）
(5) 2-(4-carboxyl benzylidene hydrazono-)-1-carboxyl Methylimidazole alkane-4-ketone
m.p.205-209℃
NMR（DMSO-d
6）δppm：
11.47（brs，1H）
8.20（s，1H）
7.49（brs，4H）
4.08（s，2H）
3.84（s，2H）
Embodiment 3
The mixture of 154mg 2-isopropylidene hydrazono-imidazolidine-4-ketone, 198mg sodium acetate, 5mg acetate and 317mg phenylacrolein was stirred 19 hours in 60 ℃.Water and chloroform are added in the reaction mixture so that mixture is distributed between them, then with water layer with further extraction three times of chloroform.Organic layer and extraction liquid merge.After the anhydrous magnesium sulfate drying mixture, the concentrating under reduced pressure mixture, the resistates that forms is contained in chromatography on the silicagel column and with mixed solvent (1: the 1 volume ratio) wash-out of chloroform and ethyl acetate, obtain 62mg 2-cinnamylidene hydrazono--5-cinnamylidene imidazolidine-4-ketone, fusing point: 154 ℃-156 ℃.
By obtaining following compound with the similar method of above-mentioned steps.
(2) 2-benzylidene hydrazono--5-benzylidene thiazolidin-4-one
NMR（DMSO-d
6）δppm：
8.49（s，1H）
7.21-7.93（m，11H）
(3) the inferior meat base of 2-hydrazono--5-cinnamylidene thiazolidin-4-one
NMR（DMSO-d
6）δppm：
12.35（brs，1H）
8.26（d，J＝8，13Hz，1H）
6.79-7.68（m，15H）
(4) 2-(4-trifluoromethyl benzylidene hydrazono-)-and 5-(4-trifluoromethyl benzylidene) thiazolidin-4-one
NMR（DMSO-d
6）δppm：
8.61（s，1H）
7.67-8.07（m，9H）
(1) mixture with 1.10g 2-benzylidene hydrazono--1-methoxycarbonyl Methylimidazole alkane-4-ketone, 520mg sodium acetate, 10ml acetate and 1.34g phenylacrolein stirred 16 hours in 60 ℃-70 ℃.
After the reaction mixture, add water and ethyl acetate inward mixture is distributed between water and the ethyl acetate, water layer is further used ethyl acetate extraction three times.Organic layer and extraction liquid merge.After the anhydrous magnesium sulfate drying mixture, the concentrating under reduced pressure mixture, resistates is contained in chromatography on the silicagel column and with mixed solvent (1: the 1 volume ratio) wash-out of normal hexane and ethyl acetate, obtains 620mg 2-cinnamylidene hydrazono--5-cinnamylidene-1-methoxycarbonyl Methylimidazole alkane-4-ketone.
NMR（CDCl
3）δppm：
8.02-8.33（m，2H）
7.18-7.78（m，12H）
6.69（d，J＝15，8Hz，1H）
5.95（d，J＝11，4Hz，1H）
4.53（s，2H）
3.81（s，3H）
(2) add 20ml methyl alcohol and 2.4ml 2N sodium hydroxide solution in the 620mg compound that makes toward above-mentioned step, mixture was in stirring at room 24 hours.The gained reaction mixture adds 1N hydrochloric acid and neutralizes.Then, the concentrating under reduced pressure reaction mixture and in ethanol recrystallization, obtain 417mg 1-carboxymethyl-2-cinnamylidene hydrazono--5-cinnamylidene imidazolidine-4-ketone, fusing point: 246 ℃-248 ℃.
Embodiment 5
(1) the 2.73g thiosemicarbazide is dissolved in after the mixture of 80ml tetrahydrofuran (THF) and 20ml water, adds the 3.57g phenylcarbimide in the solution, then in stirring at room 6 hours.Concentrating under reduced pressure gained reaction mixture adds in the resistates that forms after the 100ml water, forms precipitation thus, and recrystallizing methanol is used in grinding, filtration, washing then, obtains the 1.80g white crystal.
(2) crystal that above-mentioned steps is obtained is dissolved in 80ml ethanol, adds after 1.26g chloracetic acid ethyl ester and the 840mg sodium sulfate, with gained reaction mixture reflux 16 hours.Cooling gained reaction product, and, obtain 1.65g 2-(4-phenylsemicarbazone by the crystal that filtered and recycled is separated out) thiazolidin-4-one.
NMR（DMSO-d
6）δppm：
11.64（brs，1H）
9.01（s，1H）
8.92（s，1H）
6.82-7.52（m，5H）
3.91（s，2H）
According to obtaining following compound with the similar method of above-mentioned steps.
(3) thiazolidin-4-one 2-(4-naphthyl semicarbazone)
NMR（DMSO-d
6）δppm：
11.56（brs，1H）
9.12（s，1H）
8.69（s，1H）
7.35-8.07（m，7H）
3.97（s，2H）
(4) semicarbazone 2-[4-(4-chloro-phenyl-)] thiazolidin-4-one
NMR（DMSO-d
6）δppm：
11.47（brs，1H）
9.02（s，2H）
7.50（d，J＝9.01Hz，2H）
7.26（d，J＝8.79Hz，2H）
3.92（s，2H）
(5) thiazolidin-4-one 2-(4-benzyl semicarbazone)
m.p.：218℃-220℃
(6) thiazolidin-4-one semicarbazone 2-[4-(4-fluorophenyl))
m.p.：223℃-225℃
(7) thiazolidin-4-one 2-(4-butyl semicarbazone)
NMR（DMSO-d
6）δppm：
11.43（brs，1H）
8.56（s，1H）
6.41（t，J＝5.9Hz，1H）
3.88（s，2H）
2.87-3.19（m，2H）
1.25（brs，4H）
0.88（t，J＝6.3Hz，3H）
Add 10ml methyl alcohol and 1ml 2N sodium hydroxide solution in 226mg 2-isopropylidene imido grpup-1-methoxycarbonyl Methylimidazole alkane-4-ketone, and with mixture in stirring at room 16 hours.Add 1N hydrochloric acid in the gained reaction mixture and neutralize, concentrating under reduced pressure, and, obtain 75mg1,4,5,7-four azabicyclos [4,3,0] ninth of the ten Heavenly Stems-5-alkene-3,8-diketone the resistates recrystallization in methyl alcohol that forms.
M.p.: be higher than 300 ℃
NMR（DMSO-d
6）δppm：
11.00（brs，1H）
11.07（brs，1H）
3.79（s，2H）
3.73（s，2H）
Embodiment 7
(1) ice-cooledly down 96mg 60% sodium hydride is suspended in 20ml dimethyl formamide (DMF), adds the 5ml DMF solution of 548mg 2-benzylidene hydrazono--1-methoxycarbonyl Methylimidazole alkane-4-ketone in the suspension gradually.Mixture after 1 hour, is added 254mg chloracetic acid ethyl ester in 30 ℃ of stirrings inward gradually, stirred 1 hour in 80 ℃ then.After the reaction mixture, add water and chloroform inward so that mixture is distributed between water and the chloroform, and water layer is further used chloroform extraction.Organic layer and extraction liquid merge, mixture places the mixed solution recrystallization of chloroform and normal hexane with anhydrous magnesium sulfate drying, concentrating under reduced pressure and with the resistates that forms, and obtains 320mg 2-benzylidene hydrazono--3-ethoxycarbonylmethyl group-1-methoxycarbonyl Methylimidazole alkane-4-ketone.
NMR（CDCl
3）δppm：
8.13（s，1H） 4.14（s，2H）
2.75-7.60（m，5H） 4.17（q，J＝5.9Hz，2H）
4.71（s，2H） 3.71（s，3H）
4.41（s，2H） 1.29（t，J＝7.0Hz，3H）
(2) add 15ml methyl alcohol and 3ml 2N sodium hydroxide solution in the compound that obtains toward above-mentioned step, and with mixture in stirring at room 2 hours.Concentrating under reduced pressure gained reaction mixture.Add in formed resistates after the 3ml water, mixture neutralizes with 1N hydrochloric acid.The filtering insolubles, again concentrating under reduced pressure filtrate and in methyl alcohol recrystallization, obtain 180mg 2-benzylidene hydrazono--1,3-dicarboxyl Methylimidazole alkane-4-ketone.
NMR（DMSO-d
6）δppm：
8.12（s，1H）
7.33-7.79（m，5H）
4.67（s，2H）
4.26（s，2H）
4.19（s，2H）
(1) add 0.5N hydrochloric acid in the 230mg 2-benzylidene hydrazono--3-ethoxy carbonyl methyl isophthalic acid-methoxy carbonyl Methylimidazole alkane-4-ketone that obtains in the step (1) of embodiment 7, and steam distillation mixture 40 minutes.Concentrating under reduced pressure gained reaction mixture, and the resistates that forms is contained in chromatography on the silicagel column and with mixture (1: the 2 volume ratio) wash-out of chloroform and ethyl acetate, obtains 60mg 7-ethoxycarbonylmethyl group-1,4,5,7-four azabicyclos [4,3,0] ninth of the ten Heavenly Stems-5-alkene-3, the 8-diketone.
m.p.188 to 193℃
NMR（DMSO-d
6）δppm：
10.24（s，1H）
4.20（s，2H）
4.04（q，J＝6.91Hz，2H）
3.98（s，2H）
1.20（t，J＝6.81Hz，3H）
(2) add 5ml ethanol and 0.3ml 2N sodium hydroxide solution in the compound that obtains thus, and with mixture in stirring at room 2 hours.Concentrating under reduced pressure gained reaction mixture, and the resistates that forms is soluble in water.Gained solution neutralizes and concentrating under reduced pressure with 1N hydrochloric acid.The resistates recrystallization in methyl alcohol that forms obtains 29mg 7-carboxymethyl-1,4,5,7-four azabicyclos [4,3,0] ninth of the ten Heavenly Stems-5-alkene-3,8-diketone.
NMR（DMSO-d
6）δppm：
8.44（brs，1H）
4.33（s，2H）
4.09（s，2H）
3.93（s，2H）
Embodiment 9
(1) ice-cooled following, 192mg 60% sodium hydride is suspended among the 20ml DMF.Add 716mg 2-isopropylidene hydrazono-thiazolidin-4-one gradually in suspension, after stirring the mixture 30 minutes, Dropwise 5 88mg chloracetic acid ethyl ester gradually in the mixture stirred 3 hours under the room temperature then.
Add water and chloroform in the gained reaction mixture so that mixture is distributed between water and the chloroform, organic layer washes twice with water, and uses anhydrous magnesium sulfate drying.Concentrating under reduced pressure water layer, the resistates of formation are contained in chromatography on the silicagel column and with mixture (10: the 1 volume ratios) wash-out of chloroform and ethyl acetate, obtain 870mg 3-ethoxy carbonyl methyl-2-isopropylidene hydrazono-thiazolidin-4-one, fusing point: 60-62 ℃.
NMR（CDCl
3）δppm：
4.49（s，2H）
4.21（q，J＝7.03Hz，2H）
3.82（s，2H）
2.01（d，J＝6.38Hz，6H）
1.26（t，J＝7.25Hz，3H）
(2) in the compound that obtains more than the 870mg, add 20ml methyl alcohol and 3ml aqueous sodium hydroxide solution down ice-cooled, and mixture was stirred 1 hour.Add 1N hydrochloric acid in the gained reaction mixture and neutralize, concentrating under reduced pressure, and resistates placed the ethanol recrystallization, obtain 280mg 3-carboxymethyl-2-isopropylidene hydrazono-thiazolidin-4-one.
NMR（DMSO-d
6）δppm：
3.97（s，2H）
3.81（s，2H）
1.97（s，6H）
According to the similar method of above-mentioned steps rapid (1) and (2), use proper raw material, obtain following compound.
(3) 5-benzylidene-2-benzylidene hydrazono--3-carboxymethyl thiazolidin-4-one
M.p.: be higher than 300 ℃
NMR（DMSO-d
6）δppm：
8.53（s，1H）
7.50 to 7.81（m，11H）
4.16（s，2H）
(4) 3-(3-carboxylic propyl group)-2-cinnamylidene hydrazono--5-cinnamylidene thiazolidin-4-one
NMR（DMSO-d
6）δppm：
7.12（d，J＝9.01Hz，1H）
6.81-7.83（m，15H）
3.93（t，J＝6.1Hz，2H）
1.71-2.38（m，4H）
(5) 3-(5-carboxy pentyl)-2-cinnamylidene hydrazono--5-cinnamylidene thiazolidin-4-one
NMR（CDCl
3）δppm：
8.21（s，1H）
6.83-7.59（m，15H）
3.91（t，J＝6.03Hz，2H）
1.44-2.54（m，8H）
Embodiment 10
Add 30ml 0.5N hydrochloric acid in the 2.0g 3-ethoxy carbonyl methyl-2-isopropylidene hydrazono-thiazolidin-4-one that obtains toward the step (1) of embodiment 9, and steam distillation mixture 15 minutes.Cooling gained reaction mixture distills out the gained precipitation, and concentrating under reduced pressure filtrate.Add saturated sodium bicarbonate solution and chloroform in the resistates that forms so that resistates is distributed between them.The organic layer water is given a baby a bath on the third day after its birth time, uses anhydrous magnesium sulfate drying, and concentrating under reduced pressure.The resistates that forms is contained in chromatography on the silicagel column and with mixture (4: the 1 volume ratios) wash-out of chloroform and ethyl acetate, obtains 870mg 3-ethoxy carbonyl methyl-2-hydrazono-thiazolidin-4-one.
NMR（DMSO-d
6）δppm：
5.26（s，2H）
4.29（s，2H）
4.12（q，J＝7.03Hz，2H）
1.19（t，J＝7.04Hz，3H）
(2) saturated sodium bicarbonate aqueous solution layer and aqueous layer are merged, the concentrating under reduced pressure mixture, and the resistates that forms is suspended in the ethanol.Filtering insolubles, filtrate decompression concentrate and in water recrystallization, obtain also [2,3-c] [1,2,4] triazine-3 of 315mg 2H-thiazole, 6(4H, 7H)-the diketone cyclic products.
NMR（DMSO-d
6）δppm：
10.79（s，1H）
4.09（s，4H）
(3) down add 15ml diox, 3ml water, 76mg salt of wormwood and 300mg 2 in the 200mg compound that obtains toward above-mentioned step (1) ice-cooled, after the 4-dinitrophenyl chloride, with mixture in stirring at room 1 hour.Concentrating under reduced pressure gained reaction mixture; the resistates that forms is contained in chromatography on the silicagel column and with mixture (1: the 1 volume ratio) wash-out of chloroform and ethyl acetate; obtain 2-(2,4-dinitrobenzene alkylsulfonyl hydrazono-)-3-ethoxy carbonyl methylthiazol alkane-4-ketone, fusing point: 163-165 ℃.
NMR（CDCl
3）δppm：
8.63（s，1H）
8.54（d，J＝8.57Hz，1H）
8.26（d，J＝8.35Hz，1H）
4.29（s，2H）
4.14（q，J＝7.01Hz，2H）
3.92（s，2H）
1.24（t，J＝7.04Hz，3H）
(4) add 5ml ethanol and 0.5ml aqueous sodium hydroxide solution in the compound that obtains toward 180mg above-mentioned steps (3), mixture was in stirring at room 20 hours.The concentrating under reduced pressure reaction mixture.In the resistates that forms, add after the water, neutralize adding 1N hydrochloric acid in the gained solution.Reclaim insolubles and water and ether washing with filtering method, obtain 130mg 3-carboxymethyl-2-(2,4-dinitrobenzene sulfo group hydrazono-) thiazolidin-4-one.
NMR（DMSO-d
6）δppm：
8.86（s，1H）
8.63（d，J＝8.57Hz，1H）
8.23（d，J＝8.57Hz，1H）
4.21（s，2H）
4.14（s，2H）
By above step (3) and (4) similar method, obtain following compound:
(5) thiazolidin-4-one 3-carboxymethyl-2-(2-oil of mirbane alkylsulfonyl hydrazono-)
NMR（CD
3OD）δppm：
7.59-8.04（m，4H）
4.21（s，2H）
3.95（s，2H）
(6) 2-(4-bromobenzenesulfonyl hydrazono-)-3-carboxymethyl thiazolidin-4-one
NMR（CD
3OD）δppm：
7.74（s，4H）
4.32（s，2H）
3.98（s，2H）
(7) 3-ethoxy carbonyl methyl-2-phenyl acetyl hydrazono-thiazolidin-4-one
m.p.200-203℃
NMR（CDCl
3）δppm：
7.24（s，5H）
4.58（s，2H）
4.19（q，J＝7.0Hz，2H）
4.01（s，2H）
3.72（s，2H）
1.23（t，J＝6.9Hz，3H）
(8) thiazolidin-4-one 3-ethoxy carbonyl methyl-2-(4-anisole alkylsulfonyl hydrazono-)
NMR（CDCl
3）δppm：
7.80（d，J＝8.79Hz，2H）
6.95（d，J＝8.79Hz，2H）
4.35（s，2H）
4.13（q，J＝7.25Hz，2H）
3.86（s，5H）
1.22（t，J＝7.0Hz，3H）
Embodiment 11
(1) adds 984mg sodium acetate, 10ml acetate and 2.54g phenylacrolein in the 1.03g 3-ethoxy carbonyl methyl-2-isopropylidene hydrazono-thiazolidin-4-one that obtains toward the step (1) of embodiment 9, and the gained reaction mixture was stirred 16 hours in 110 ℃-120 ℃.In the reaction mixture that obtains thus, add 20ml water, the precipitation that forms by filtered and recycled and be placed on benzene and the mixed solution of normal hexane in recrystallization, obtain 810mg 3-ethoxy carbonyl methyl-2-cinnamylidene hydrazono--5-cinnamylidene thiazolidin-4-one pale yellow crystals, fusing point: 210 ℃-212 ℃.
(2) then, the similar approach according to embodiment 2 steps (2) obtains 3-carboxymethyl-2-cinnamylidene hydrazono--5-cinnamylidene thiazolidin-4-one.
M.p.: be higher than 300 ℃
NMR（DMSO-d
6）δppm：
8.29（d，J＝8.13Hz，1H）
6.89-7.72（m，15H）
4.48（s，2H）
Obtain following compound according to the above-mentioned steps similar approach.
(3) 3-carboxymethyl-2-(4-fluorine benzylidene hydrazono-)-and 5-(4-fluorine benzylidene) thiazolidin-4-one
NMR（DMSO-d
6）δppm：
8.53（s，1H）
7.22-7.89（m，9H）
4.13（s，2H）
Embodiment 12
Under ice-cooled, in 1.31g 2-hydrazono-thiazolidin-4-one, add 20ml ether, 5ml water, 840mg sodium bicarbonate and 3.20g 2,4-dinitrophenyl chloride, and the gained mixture stirred 2 hours in above same temperature is then in stirring at room 20 hours.Concentrating under reduced pressure gained reaction mixture adds water and ethyl acetate in the resistates that forms so that mixture is distributed between water and the ethyl acetate.The organic layer water is given a baby a bath on the third day after its birth time, uses anhydrous magnesium sulfate drying, again concentrating under reduced pressure.The resistates that forms places the mixed solution recrystallization of second alcohol and water to obtain 600mg 2-(2,4-dinitrobenzene alkylsulfonyl hydrazono-) the light yellow needle-like crystal of thiazolidin-4-one, fusing point: 204 ℃-206 ℃.
Similar approach according to above-mentioned steps obtains following compound:
(2) thiazolidin-4-one 2-(4-tosyl group hydrazono-), fusing point: 163 ℃-165 ℃.
(3) 2-(2,4-dinitrobenzene alkylsulfonyl hydrazono-) imidazolidine-4-ketone.
NMR（DMSO-d
6）δ：
8.85（s，1H）
8.69（d，J＝8.5Hz，1H）
8.31（d，J＝8.58Hz，1H）
3.87（s，2H）
Embodiment 13
(1) mixture of the 514mg 3-ethoxycarbonylmethyl group that embodiment 9 steps (1) are obtained-2-isopropylidene hydrazono-thiazolidin-4-one, 197mg sodium acetate, 10ml acetate and 393mg terephthalic acid methyl esters stirred 3 hours in 80 ℃.Cooling gained reaction mixture adds water inward, and the crystal that will separate out thus filters and water and ether washing, obtains 710mg 3-ethoxycarbonylmethyl group-2-(4-methoxycarbonyl benzylidene hydrazono-) thiazolidin-4-one.
(2), obtain 2-(4-carboxyl benzylidene hydrazono-according to the similar hydrolysis reaction of embodiment 2 steps (2))-3-carboxymethyl thiazolidin-4-one.
NMR（DMSO-d
6）δppm：
8.52（s，1H）
7.71-8.12（m，4H）
4.41（s，2H）
4.09（s，2H）
Similar approach according to above-mentioned steps (1) and (2) obtains following compound.
(3) 3-carboxymethyl-2-salicylidene hydrazono-thiazolidin-4-one
m.p.258-263℃
NMR（DMSO-d
6）δppm：
10.72（s，1H）
8.68（s，1H）
6.83-7.63（m，4H）
4.40（s，2H）
4.14（s，2H）
Embodiment 14
(1) similar approach according to embodiment 9 steps (1) obtains 3-cyclopentyl-2-isopropylidene hydrazono-thiazolidin-4-one, fusing point: 61 ℃-63 ℃.
Obtain following compound according to above similar approach:
(2) 2-isopropylidene hydrazono--3-phenoxy group acetylthiazole alkane-4-ketone
m.p.172 to 175℃
NMR（CDCl
3）δppm：
6.89-7.26（m，5H）
4.84（s，2H）
4.15（s，2H）
2.02（s，6H）
(3) 2-isopropylidene hydrazono--3-methoxycarbonyl phenoxy group acetylthiazole alkane-4-ketone
NMR（CDCl
3）δppm：
7.98（d，J＝8.35Hz，2H）
6.94（d，J＝8.35Hz，2H）
4.89（s，2H）
4.16（s，2H）
3.87（s，3H）
2.01（s，6H）
(4) 2-isopropylidene hydrazono--1-methoxycarbonyl methyl-3-Methylimidazole alkane-4-ketone
m.p.90 92℃
NMR（CDCl
3）δppm：
4.58（s，2H）
3.95（s，2H）
3.72（s，3H）
3.07（s，3H）
1.93（d，J＝2.64Hz，6H）
(5) 2-isopropylidene hydrazono--3-Methylimidazole alkane-4-ketone
NMR（CDCl
3）δppm：
5.65（brs，1H）
3.97（s，2H）
3.11（s，3H）
2.02（d，J＝2.63Hz，6H）
(6) 2-isopropylidene hydrazono--1,3-methylimidazole alkane-4-ketone
NMR（CDCl
3）δppm：
3.83（s，2H）
3.37（s，3H）
3.05（s，3H）
1.99（s，6H）
Embodiment 15
To [see Can.J.Chem. with known method, 37,1597-1607(1959)] mixture of 716mg 2-isopropylidene hydrazono-thiazolidin-4-one, 394mg sodium acetate, 10ml acetate and the 720mg terephthalylidene aldehydic acid that synthesizes stirred 16 hours in 80 ℃.Add water and chloroform in the gained reaction mixture so that mixture is distributed between water and the chloroform.Water layer is used chloroform extraction three times in addition.Organic layer and extraction liquid merge, and mixture is with anhydrous magnesium sulfate drying and concentrating under reduced pressure.The resistates that forms is contained in chromatography and usefulness chloroform and methanol mixture (50: 1 volume ratios) wash-out on the silicagel column, obtains 1-(4-carboxyl benzylidene hydrazono-) thiazolidin-4-one, fusing point: be higher than 300 ℃.
NMR（DMSO-d
6）δppm：
8.46（s，1H）
7.77-8.12（m，4H）
3.91（s，2H）
Obtain following compound according to above-mentioned similar approach:
(2) thiazolidin-4-one 2-(4-carboxyl phenoxy group ethylidene hydrazono-)
m.p.255-260℃
NMR（DMSO-d
6）δppm：
12.20（brs，1H）
7.83-7.93（m，3H）
7.06（d，J＝8.57Hz，2H）
4.86（d，J＝4.62Hz，2H）
3.85（s，2H）
(3) 2-(3,4,5-trimethoxy benzylidene hydrazono-) thiazolidin-4-one
NMR（DMSO-d
6）δppm：
11.87（brs，1H）
8.29（s，1H）
7.07（s，2H）
3.81（s，9H）
3.71（s，2H）
(4) 2-phenyl propylidene hydrazono-thiazolidin-4-one
NMR（DMSO-d
6）δppm：
11.69（brs，1H）
7.71（t，J＝5.1Hz，1H）
7.23（s，5H）
3.80（s，2H）
2.49-2.83（m，4H）
(5) thiazolidin-4-one 2-(2-nitro cinnamylidene hydrazono-)
NMR（DMSO-d
6）δppm：
7.0-8.25（m，7H）
3.81（s，2H）
Embodiment 16
Same quadrat method according to embodiment 4 steps (1); but the 2-(2 that uses embodiment 10 steps (3) to obtain; 4-dinitrobenzene alkylsulfonyl hydrazono-)-3-ethoxycarbonylmethyl group imidazolidine-4-ketone; obtain 5-cinnamylidene-2-(2,4-dinitrobenzene alkylsulfonyl hydrazono-)-3-ethoxy carbonyl methylthiazol alkane-4-ketone.
NMR（CDCl
3）δppm：
8.68（s，1H）
8.55（d，J＝8.35Hz，1H）
8.27（d，J＝8.57Hz，1H）
6.63-7.60（m，8H）
4.41（s，2H）
4.15（q，J＝6.81Hz，2H）
1.23（t，J＝5.49Hz，3H）
Obtain following compound by above similar approach:
(2) 2-(2,4-dinitrobenzene alkylsulfonyl hydrazono-)-3-ethoxy carbonyl methyl-5-(2-Alpha-Methyl cinnamylidene) thiazolidin-4-one
NMR（CDCl
3）δppm：
8.69（s，1H）
8.55（d，J＝8.79Hz，1H）
8.28（d，J＝7.92Hz，1H）
6.80 to 7.59（m，7H）
4.42（s，2H）
4.15（q，J＝7.25Hz，2H）
2.30（s，3H）
1.23（t，J＝6.59Hz，3H）
Pharmacological testing 1
Measure the effect of compound of the present invention and comparative compound vitro inhibition Maillard reaction in accordance with the following methods.That is to say, with concentration be the bovine serum albumin(BSA) of 100mg/ml, glucose that concentration is 400mM and 5mM test compound be dissolved in pH7.4 the 0.5M sodium phosphate buffer in, and with mixture in 37 ℃ of 2 weeks of insulation.In used test compound, embodiment 1(3), embodiment 5(3 embodiment 2(5)) and (4), embodiment 6(1), embodiment 9(2), embodiment 10(5), embodiment 12(1) and embodiment 15(1) compound each separate and in 37 ℃ of insulations 12 days so that the concentration of 6mM is dense.After insulation finishes, with containing 0.01%(W/V) phosphate buffered saline buffer of Tween 80 is 100 times of dilutions of nutrient solution, measures the fluorescence of gained solution under 370nm is excited wavelength and 440nm wavelength of fluorescence.
Be calculated as follows the inhibition percentage:
Inhibiting rate (%)={ [(A-B)-(C-D)]/(A-B) } * 100
Wherein:
A:(bovine serum albumin(BSA)+glucose) fluorescence
B: the fluorescence of bovine serum albumin(BSA)
C:(bovine serum albumin(BSA)+glucose+test compound) fluorescence
D:(bovine serum albumin(BSA)+test compound) fluorescence
The results are shown in following table 1.
Table 1
Embodiment numbers inhibiting rate (%) embodiment and numbers inhibiting rate (%)
1(1) 91 3(2) 24
1(2) 10 3(3) 5
1(3) 26 3(4) 9
1(4) 10 4(1) 5
1(5) 27 4(2) 88
1(6) 13 5(2) 11
1(7) 4 5(3) 43
1(8) 7 5(4) 44
1(9) 8 5(5) 7
1(10) 18 5(6) 54
1(11) 39 5(7) 5
2(1) 2 6(1) 70
2(2) 4 7(1) 9
2(3) 25 7(2) 2
2(4) 6 8(1) 10
2(5) 46 8(2) 17
3(1) 49
Table 1(is continuous)
Embodiment numbers inhibiting rate (%) embodiment and numbers inhibiting rate (%)
9(1) 34 13(1) 12
9(2) 63 13(2) 33
9(3) 59 13(3) 41
9(4) 95 14(1) 27
9(5) 89 14(2) 5
10(1) 22 14(3) 10
10(2) 16 14(4) 3
10(3) 86 14(5) 82
10(4) 69 14(6) 33
10(5) 59 15(1) 67
10(6) 14 15(2) 43
10(7) 13 15(3) 24
10(8) 12 15(4) 10
11(1) 7 15(5) 43
11(2) 81 16(1) 89
11(3) 30 16(2) 95
12 (1) 92 compounds 1
*61
12 (2) 26 compounds 2
*73
12 (3) 93 compounds 3
*41
* test compound
Compound 1:
2-hydrazono-thiazolidin-4-one
Compound 2:
2-isopropylidene hydrazono-thiazolidin-4-one
Compound 3:
2-hydrazono-imidazolidine-4-ketone
According to people such as T.Soulis-Liparota at Diabetes, (Vol.40, pp.1328-1334, in October, 1991) and people such as D.Edelstein at Diabetologia[(1992) 35:96-97) method introduced, in the trouble rats with diabetes that suis (Streptozocin) is brought out, measure compound of the present invention according to urinary albumin excretion.
Test method
Give heavily be 170g-200g by the dosage intravenous injection suis (STZ) of the male SD rat of fasting with 50mg/kg, after six days, show that blood-sugar content is that 200mg/dl or above rat are used for testing.The trouble rats with diabetes of bringing out for STZ is analyzed according to ELISA(enzyme bonded immunosorbent) measure albumin content in 24 hours the urine of savings.Rat is divided into two groups; one group (n=7) usefulness test compound-embodiment 12(1) 2-(2 of preparation; 4-dinitrobenzene alkylsulfonyl hydrazono-) normal saline solution (containing 0.10%Polysorbate 80) of thiazolidin-4-one is with the dosed administration of 10mg/kg, and another group (n=7) usefulness does not contain above-mentioned solution (contrast) administration of test compound.Also have, untreated male SD rat is as normal control group (n=6).Comparative research carried out for 6 weeks, simultaneously to dosing group and 1 day 1 time this solution of intravenous injection of control group.
Test-results
Gained the results are shown in the accompanying drawing.From the result of accompanying drawing as can be seen, behind test compound administration fortnight, the dosing group (in the accompanying drawing with-●-expression) in observe urinary albumin excretory restraining effect.Afterwards, this effect continues, and finishes until 6 trial periods in week.At last, with comparing of control group (usefulness-zero in the accompanying drawing-represent), observe urinary albumin excretory 54% restraining effect.
Preparation example
Mix following component by usual manner, with pelleter the gained mixture is pressed into 100, every contains the 50mg activeconstituents.
Embodiment 10(3) compound 5g
Sodium Lauryl Sulphate BP/USP 0.2g
Magnesium Stearate 0.2g
The plain 4.6g of crystal fibre
Although describe the present invention in detail according to specific embodiment, under the situation that does not deviate from its spirit and scope, this area professional can easily make various changes and remodeling.
Claims (20)
1, the compound or its salt of formula (1) expression:
R wherein
1Represent the phenoxy group low-grade alkane acidyl that can have lower alkoxycarbonyl on hydrogen atom, low alkyl group, carboxyl low-grade alkyl, lower alkoxycarbonyl low alkyl group, the phenyl ring, or low-grade cycloalkyl; R
2Representative-NHR
4(R wherein
4Represent hydrogen atom; Can have 1-3 substituent phenyl sulfonyl on the phenyl ring, described substituting group is selected from halogen atom, nitro, lower alkoxy and low alkyl group; The phenyl low-grade alkane acidyl or-CO-NHR
5, R wherein
5Represent phenyl, the phenyl lower alkyl that can have halogen atom on low alkyl group, the phenyl ring, or naphthyl) or-N=R
6(R wherein
6Represent low-grade alkylidene, the low-grade alkylidene that has 1 or 2 low-grade cycloalkyl, can have 1-3 substituent phenyl low-grade alkylidene on the phenyl ring, described substituting group is selected from halogen atom, carboxyl, lower alkoxycarbonyl, nitro, hydroxyl, lower alkoxy and junior alkyl halides, the phenyl lower alkenylene that can have nitro on the phenyl ring, lower alkenylene, rudimentary ring alkylidene group, or can have the phenoxy group low-grade alkylidene of carboxyl on the phenyl ring); R
3Represent two hydrogen atoms, can have the phenyl low-grade alkylidene of halogen atom or junior alkyl halides on the phenyl ring, or the phenyl lower alkenylene; And X representative-S-or-N (R
7)-(be R wherein
7Represent hydrogen atom, low alkyl group, carboxyl low-grade alkyl or lower alkoxycarbonyl low alkyl group); And, R
1And R
4, or R
4And R
7Can mutually combine forms the oxygen ethylidene, and condition is to work as R
1Be hydrogen atom, R
3Be two hydrogen atoms and X when being, R
2Be not-NHR
4(R wherein
4Be the phenyl sulfonyl that can have lower alkoxy on hydrogen atom or the phenyl ring) or-NH=R
6(R wherein
6Represent low-grade alkylidene, can have the phenyl low-grade alkylidene of halogen atom, base, hydroxyl or lower alkoxy on the phenyl ring, or can have the lower alkenylene of nitro on the phenyl ring); And work as R
1Be hydrogen atom, R
2Be-N=R
6And X is-S-or-during NH-, R
3And R
6Can not be the phenyl low-grade alkylidene simultaneously; Have again, work as R
2Be-NHR
4, R
3Be two hydrogen atoms and X be-during S-, R
1And R
4Be not incorporated into the oxygen ethylidene.
2, according to the described compound or its salt of claim 1, wherein R
1Be hydrogen atom, low alkyl group, carboxyl low-grade alkyl or lower alkoxycarbonyl low alkyl group; R
2Be-NHR
4Or-N=R
6(R wherein
6Be low-grade alkylidene, have the phenyl low-grade alkylidene that can have carboxyl on the low-grade alkylidene, phenyl ring of 1 or 2 low-grade cycloalkyl, phenyl lower alkenylene, lower alkenylene or rudimentary ring alkylidene group); R
3Be two hydrogen atoms or phenyl lower alkenylene; And X is-N(R
1)-; R
1And R
4Be not incorporated into the oxygen ethylidene; And work as R
2Be-NHR
4The time, R
4And R
7Be incorporated into the oxygen ethylidene.
3, according to the described compound or its salt of claim 1, wherein R
1Be hydrogen atom, carboxyl low-grade alkyl, the lower alkoxycarbonyl low alkyl group can have the phenoxy group low alkyl group acyl group of lower alkoxycarbonyl on the phenyl ring; R
2Be-NHR
4Or-N=R
6(R wherein
6Be low-grade alkylidene, can have the phenyl low-grade alkylidene of halogen atom, carboxyl, lower alkoxycarbonyl, hydroxyl or junior alkyl halides on the phenyl ring, can have the phenoxy group low-grade alkylidene that can have carboxyl on the phenyl lower alkenylene of nitro or the phenyl ring on the phenyl ring); X is-S-; And R
1And R
4, or R
4And R
7Be not incorporated into the oxygen ethylidene.
4, according to the described compound or its salt of claim 2, wherein R
2Be-N=R
6
5, according to the described compound or its salt of claim 2, wherein R
1Be hydrogen atom, carboxyl low-grade alkyl or lower alkoxycarbonyl low alkyl group; R
2Be-NHR
4; And R
3Be two hydrogen atoms.
6, according to the described compound or its salt of claim 3, wherein R
1Be hydrogen atom, R
2Be-NHR
4(R wherein
4Be can have on the phenyl ring nitro or low alkyl group benzenesulfonyl or-CO-NHR
6) or-N=R
6(R wherein
6Be the phenoxy group low-grade alkylidene that can have carboxyl on the phenyl ring); And R
3Be two hydrogen atoms.
7, according to the described compound or its salt of claim 3, wherein R
1Be carboxyl low-grade alkyl, the lower alkoxycarbonyl low alkyl group can have the phenoxy group low-grade alkane acidyl of lower alkoxycarbonyl on the phenyl ring, or low-grade cycloalkyl, R
2Be-NHR
4(R wherein
4Be hydrogen atom, can have the benzenesulfonyl of halogen atom, nitro or lower alkoxy on the phenyl ring, or the phenyl low-grade alkane acidyl) or-N=R
6(R wherein
6Be low-grade alkylidene, or can have carboxyl on the phenyl ring, the phenyl low-grade alkylidene of lower alkoxycarbonyl or hydroxyl); R
3Be two hydrogen atoms.
8, according to the described compound or its salt of claim 3, wherein R
1Be hydrogen atom, carboxyl low-grade alkyl or lower alkoxycarbonyl low alkyl group; R
2Be-NHR
4(R wherein
4Be the benzenesulfonyl that can have nitro on hydrogen atom or the phenyl ring) or-N=R
6(R wherein
6Be the phenyl low-grade alkylidene that can have halogen atom or junior alkyl halides on the phenyl ring, or the phenyl lower alkenylene); R
3Be the phenyl low-grade alkylidene that can have halogen atom or junior alkyl halides on the phenyl ring, or the phenyl lower alkenylene.
9, according to the described compound or its salt of claim 3, wherein R
2Be-NHR
4(R wherein
4Be can have on the phenyl ring 1-3 be selected from halogen atom, nitro, lower alkoxy and low-grade alkyl substituent the phenyl ring acyl group or-N=R
6(R wherein
6Be low-grade alkylidene).
10, according to the described compound or its salt of claim 9, wherein R
2Be-NHR
4, R wherein
4It is the benzenesulfonyl that has nitro on the phenyl ring.
11, according to the described compound or its salt of claim 4, wherein R
1Be hydrogen atom, R
3Be two hydrogen atoms and R
6It is low-grade alkylidene.
12, according to the described compound or its salt of claim 11, wherein R
1It is hydrogen atom.
13, according to the described compound or its salt of claim 12, wherein said compound is 2-isopropylidene hydrazono-imidazolidine-4-ketone.
14, according to the described compound or its salt of claim 6, wherein R
2Be-NHR
4(R wherein
4Be the benzenesulfonyl that has nitro or low alkyl group on the phenyl ring).
15, according to the described compound or its salt of claim 14, wherein said compound is 2-(2,4-dinitrobenzene alkylsulfonyl hydrazono-) thiazolidin-4-one.
16, the method for the compound or its salt of a kind of preparation following formula (1) expression,
R wherein
1Represent the phenoxy group low-grade alkane acidyl that can have lower alkoxycarbonyl on hydrogen atom, low alkyl group, carboxyl low-grade alkyl, lower alkoxycarbonyl low alkyl group, the phenyl ring, or low-grade cycloalkyl; R
2Representative-NHR
4(R wherein
4Represent hydrogen atom; Can have 1-3 substituent phenyl sulfonyl on the phenyl ring, described substituting group is selected from halogen atom, nitro, lower alkoxy and low alkyl group; The phenyl low-grade alkane acidyl or-CO-NHR
5, R wherein
5Represent phenyl, the phenyl lower alkyl that can have halogen atom on low alkyl group, the phenyl ring, or naphthyl) or-N=R
6(R wherein
6Represent low-grade alkylidene, the low-grade alkylidene that has 1 or 2 low-grade cycloalkyl, can have 1-3 substituent phenyl low-grade alkylidene on the phenyl ring, described substituting group is selected from halogen atom, carboxyl, lower alkoxycarbonyl, nitro, hydroxyl, lower alkoxy and junior alkyl halides, the phenyl lower alkenylene that can have nitro on the phenyl ring, lower alkenylene, rudimentary ring alkylidene group, or can have the phenoxy group low-grade alkylidene of carboxyl on the phenyl ring); R
3Represent two hydrogen atoms, can have the phenyl low-grade alkylidene of halogen atom or junior alkyl halides on the phenyl ring, or the phenyl lower alkenylene; And X representative-S-or-N(R
7)-(be R wherein
7Represent hydrogen atom, low alkyl group, carboxyl low-grade alkyl or lower alkoxycarbonyl low alkyl group); And, R
1And R
4, or R
4And R
7Can mutually combine forms the oxygen ethylidene, and condition is to work as R
1Be hydrogen atom, R
3Be two hydrogen atoms and X be-during S-, R
2Be not-NHR
4(R wherein
4Be the phenyl sulfonyl that can have lower alkoxy on hydrogen atom or the phenyl ring) or-NH=R
6(R wherein
6Represent low-grade alkylidene, can have the phenyl low-grade alkylidene of halogen atom, nitro, hydroxyl or lower alkoxy on the phenyl ring, or can have the phenyl lower alkenylene of nitro on the phenyl ring); And work as R
1Be hydrogen atom, R
2Be-N=R
6And X is-S-or-during NH-, R
3And R
6Can not be the phenyl low-grade alkylidene simultaneously; Have again, work as R
2Be-NHR
4, R
3Be two hydrogen atoms and X be-during S-, R
1And R
4Be not incorporated into the oxygen ethylidene.
This method comprises the reactions steps that is selected from following (I)-(IX)
(I) a kind of reaction, this reaction comprise makes formula (2) compound
With the reaction of formula (3) compound,
To obtain formula (1a) compound:
R wherein
1, R
2And R
7Identical with definition in the claim 1, and R
8Represent the ester residue;
(II) a kind of reaction, this reaction comprise makes formula (4) compound
With the reaction of formula (5) compound,
To obtain formula (1b) compound:
R wherein
1And R
2Identical with definition in the claim 1, R
8Represent the ester residue, and Y represents halogen atom;
(III) a kind of reaction, this reaction comprise makes formula (1c) compound
React with formula (6) compound
To obtain formula (1d) compound:
R wherein
1, R
6Identical with X with definition in the claim 1, and A represents halogen atom;
(IV) a kind of reaction, this reaction comprise makes formula (1d) compound
With the reaction of formula (7) compound,
To obtain formula (1e) compound:
R wherein
2Identical with X with definition in the claim 1, R
6aRepresent low-grade alkylidene, and R
6bRepresent to have the phenyl low-grade alkylidene that 1-3 is selected from halogen atom, carboxyl, nitro, hydroxyl, lower alkoxy and halogenated lower alkoxy on the phenyl ring, the phenyl lower alkenylene, or can have the phenoxy group low-grade alkylidene of carboxyl on the phenyl ring,
(V) a kind of reaction, this reaction comprise makes formula (1f) compound
With the reaction of formula (8) compound,
To obtain (1g) compound:
R wherein
1Identical with X with definition in the claim 1; R
2aRepresentative-N=R
6a,-N=R
6b, or-NHR
4a(R wherein
6bDefine as above R
6aRepresent low-grade alkylidene, and R
4aRepresent and to have 1-3 benzenesulfonyl that is selected from halogen atom, nitro, lower alkoxy and low-grade alkyl substituent on the phenyl ring); R
3aRepresent the phenyl low-grade alkylidene that can have junior alkyl halides on the phenyl ring, or the phenyl lower alkenylene; And R
2bRepresentative-N=R
3a,-N=R
6bOr-NHR
4a(R wherein
3a, R
6b, and R
4aDefinition as above);
(VI) a kind of reaction, this reaction comprise makes formula (1d ') compound
With a kind of acidic cpd reaction, to obtain formula (1h) compound:
R wherein
1, R
3, R
6Identical with X with definition in the claim 1;
(VII) a kind of reaction, this reaction comprise makes formula (1h) compound
With the reaction of formula (9) compound,
To obtain formula (1i) compound:
R wherein
1, R
3Identical with X with definition in the claim 1, R
9Represent and to have 1-3 phenyl that is selected from halogen atom, nitro, lower alkoxy and low-grade alkyl substituent on the phenyl ring; And B represents halogen atom;
(VIII) a kind of reaction, this reaction comprise cyclisation formula (1j) compound,
To obtain formula (1k) compound
R wherein
3, R
6Identical with X with definition in the claim 1, and R
10Represent low alkyl group, and
(IX) a kind of reaction, this reaction comprise cyclisation formula (1e) compound,
R wherein
1, R
3, R
6Identical with X with definition in the claim 1, and R
10Represent low alkyl group.
17, a kind of inhibition composition of Maillard reaction in vivo, it comprises the described compound or its salt of claim 1 and the pharmaceutical carrier of significant quantity.
18, according to the described inhibition of claim 17 composition of Maillard reaction in vivo, wherein said composition is a kind of medicament for the treatment of the complication of diabetes-induced.
19, a kind of inhibition method of Maillard reaction in vivo, this method comprises the compound or its salt of use formula (1 ') representative:
R wherein
1Represent the phenoxy group low-grade alkane acidyl that can have lower alkoxycarbonyl on hydrogen atom, low alkyl group, carboxyl low-grade alkyl, lower alkoxycarbonyl low alkyl group, the phenyl ring, or low-grade cycloalkyl; R
2Representative-NHR
4(R wherein
4Represent hydrogen atom; Can have 1-3 substituent phenyl sulfonyl on the phenyl ring, described substituting group is selected from halogen atom, nitro, lower alkoxy and low alkyl group; The phenyl low-grade alkane acidyl or-CO-NHR
5, R wherein
5Represent phenyl, the phenyl lower alkyl that can have halogen atom on low alkyl group, the phenyl ring, or naphthyl) or-N=R
6(R wherein
6Represent low-grade alkylidene, the low-grade alkylidene that has 1 or 2 low-grade cycloalkyl, can have 1-3 substituent phenyl low-grade alkylidene on the phenyl ring, described substituting group is selected from halogen atom, carboxyl, lower alkoxycarbonyl, nitro, hydroxyl, lower alkoxy and junior alkyl halides, the phenyl lower alkenylene that can have nitro on the phenyl ring, lower alkenylene, rudimentary ring alkylidene group, or can have the phenoxy group low-grade alkylidene of carboxyl on the phenyl ring); R
3Represent two hydrogen atoms, can have the phenyl low-grade alkylidene of halogen atom or junior alkyl halides on the phenyl ring, or the phenyl lower alkenylene; And X representative-S-or-N(R
7)-(be R wherein
7Represent hydrogen atom, low alkyl group, carboxyl low-grade alkyl or lower alkoxycarbonyl low alkyl group); And, R
1And R
4, or R
4And R
7Can mutually combine and form the oxygen ethylidene.
20, according to the described inhibition of claim 19 method of Maillard reaction in vivo, wherein this method is a kind of methods of treatment of diabetes-induced complication.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21562191 | 1991-08-27 | ||
| JP215621/91 | 1991-08-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1069728A true CN1069728A (en) | 1993-03-10 |
| CN1034864C CN1034864C (en) | 1997-05-14 |
Family
ID=16675440
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92110177A Expired - Fee Related CN1034864C (en) | 1991-08-27 | 1992-08-27 | Maillard reaction inhibitor |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US5422360A (en) |
| EP (1) | EP0531812A1 (en) |
| KR (1) | KR930004286A (en) |
| CN (1) | CN1034864C (en) |
| AU (1) | AU649158B2 (en) |
| CA (1) | CA2077032A1 (en) |
| TW (1) | TW221689B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106620745A (en) * | 2015-11-02 | 2017-05-10 | 中国石油化工股份有限公司 | Method for reducing Maillard reaction during culture medium sterilization process |
| CN107522311A (en) * | 2017-10-19 | 2017-12-29 | 王云龙 | A kind of water purifier |
| CN114315753A (en) * | 2020-09-30 | 2022-04-12 | 烟台药物研究所 | Compound, and synthetic method and application thereof |
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| ATE220327T1 (en) * | 1992-09-29 | 2002-07-15 | Inhale Therapeutic Syst | PULMONARY RELEASE OF ACTIVE FRAGMENTS OF THE PARATHORMONE |
| DE69429641T2 (en) * | 1993-02-26 | 2002-08-29 | Otsuka Pharma Co Ltd | THIAZOLE OR IMIDAZOLE DERIVATIVES AS MAILLARD REACTION INHIBITORS |
| US20030113273A1 (en) * | 1996-06-17 | 2003-06-19 | Patton John S. | Methods and compositions for pulmonary delivery of insulin |
| GB2288732B (en) * | 1994-04-13 | 1998-04-29 | Quadrant Holdings Cambridge | Pharmaceutical compositions |
| US6290991B1 (en) | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
| US5955617A (en) * | 1996-05-21 | 1999-09-21 | Pharmacia & Upjohn Company | Aminoguanidine carboxylate lactams for the treatment of non-insulin-dependent diabetes mellitus |
| AU6518598A (en) * | 1997-03-28 | 1998-10-22 | Otsuka Pharmaceutical Co., Ltd. | Age production inhibitory composition comprising a maillard reaction inhibitor and vitamin b6 |
| US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
| US20060165606A1 (en) | 1997-09-29 | 2006-07-27 | Nektar Therapeutics | Pulmonary delivery particles comprising water insoluble or crystalline active agents |
| CA2382133C (en) | 2000-05-10 | 2010-11-23 | Alliance Pharmaceutical Corporation | Phospholipid-based powders for drug delivery |
| US8404217B2 (en) | 2000-05-10 | 2013-03-26 | Novartis Ag | Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use |
| US7871598B1 (en) | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
| ES2364636T3 (en) | 2001-12-19 | 2011-09-08 | Novartis Ag | PULMONARY ADMINISTRATION OF AMINOGLUCOSIDS. |
| USRE43833E1 (en) | 2003-11-21 | 2012-11-27 | Actelion Pharmaceuticals Ltd. | Thiazolidin-4-one derivatives |
| BRPI0416752B8 (en) | 2003-11-21 | 2021-05-25 | Actelion Pharmaceuticals Ltd | pharmaceutical composition, use of one or more compounds, and compounds |
| US8912340B2 (en) | 2006-11-23 | 2014-12-16 | Actelion Pharmaceuticals Ltd. | Process for the preparation of 2-imino-thiazolidin-4-one derivatives |
| DK2094676T3 (en) * | 2006-11-23 | 2013-06-10 | Actelion Pharmaceuticals Ltd | NEW PROCEDURE FOR THE PREPARATION OF 2-IMINOTHIAZOLIDIN-4-ON DERIVATIVES |
| MX350891B (en) | 2012-08-17 | 2017-09-22 | Actelion Pharmaceuticals Ltd | Process for the preparation of|(2z,5z)-5-(3-chloro-4-((r)-2,3-dih ydroxypropoxy)benzylidene)-2-(propylimino)-3-|(o-tolyl)thiazolid in-4-one and intermediate used in said process. |
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| GB132914A (en) * | ||||
| DE381628C (en) * | 1923-09-22 | Gegauf & Co | Needle clip for hand embroidery machines | |
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| GB181779A (en) * | 1921-02-19 | 1922-06-19 | Henry Ramsden | Improvements in covers or gaiters for laminated vehicle springs |
| DE929549C (en) * | 1951-11-29 | 1955-08-01 | Hoechst Ag | Process for the preparation of substituted pseudothiohydantoins and their hydrohalides |
| DE932674C (en) * | 1952-12-06 | 1955-09-05 | Hoechst Ag | Process for the preparation of N-alkoxyphenyl-pseudothiohydantoins |
| US2739971A (en) * | 1954-03-29 | 1956-03-27 | Eastman Kodak Co | 5-benzal-3-n-cetyl-2-phenylimino-4-thiazolidone |
| DE1038050B (en) * | 1955-11-17 | 1958-09-04 | Farmaceutici Italia S A Soc | Process for the preparation of 5- (3 ', 4'-dioxybenzylidene) derivatives of heterocyclic compounds |
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| US4402964A (en) * | 1981-11-16 | 1983-09-06 | Mcneilab, Inc. | N-Aryl-N'-(3-methyl or ethyl-4-oxothiazolidinylidene)ureas useful for the treatment of epilepsy |
| DE3146299A1 (en) * | 1981-11-17 | 1983-06-01 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | THIAZOLO- AND (1,3) THIAZINO (2,3-C) (1,2,4) TRIAZINONE WITH SELECTIVE HERBICIDAL ACTION AND METHOD FOR PRODUCING THESE COMPOUNDS |
| DE3302413A1 (en) * | 1983-01-21 | 1984-07-26 | Schering AG, 1000 Berlin und 4709 Bergkamen | TRIAZINONE, METHOD FOR PRODUCING THESE COMPOUNDS AND THEIR CONTAINING MEANS WITH SELECTIVE HERBICIDAL ACTION |
| GB8311443D0 (en) * | 1983-04-27 | 1983-06-02 | Smith Kline French Lab | Chemical compounds |
| US4908446A (en) * | 1985-11-14 | 1990-03-13 | The Rockefeller University | Inhibitors of nonenzymatic cross-linking |
| US4758583A (en) * | 1984-03-19 | 1988-07-19 | The Rockefeller University | Method and agents for inhibiting protein aging |
| DE3446812A1 (en) * | 1984-12-21 | 1986-06-26 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW IMIDAZO DERIVATIVES, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
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| JPS6456614A (en) * | 1987-08-27 | 1989-03-03 | Ono Pharmaceutical Co | Maillard reaction inhibitor |
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| DE3841879A1 (en) * | 1988-12-13 | 1990-06-21 | Boehringer Mannheim Gmbh | NEW IMIDAZOLIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, AND MEDICAMENTS CONTAINING SUCH COMPOUNDS |
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-
1992
- 1992-08-21 TW TW081106619A patent/TW221689B/zh active
- 1992-08-26 AU AU21311/92A patent/AU649158B2/en not_active Ceased
- 1992-08-27 CA CA002077032A patent/CA2077032A1/en not_active Abandoned
- 1992-08-27 KR KR1019920015455A patent/KR930004286A/en not_active Application Discontinuation
- 1992-08-27 CN CN92110177A patent/CN1034864C/en not_active Expired - Fee Related
- 1992-08-27 EP EP92114614A patent/EP0531812A1/en not_active Ceased
-
1993
- 1993-07-23 US US08/095,994 patent/US5422360A/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106620745A (en) * | 2015-11-02 | 2017-05-10 | 中国石油化工股份有限公司 | Method for reducing Maillard reaction during culture medium sterilization process |
| CN106620745B (en) * | 2015-11-02 | 2019-10-11 | 中国石油化工股份有限公司 | A kind of method of Maillard reaction during reduction medium sterilization |
| CN107522311A (en) * | 2017-10-19 | 2017-12-29 | 王云龙 | A kind of water purifier |
| CN114315753A (en) * | 2020-09-30 | 2022-04-12 | 烟台药物研究所 | Compound, and synthetic method and application thereof |
| CN114315753B (en) * | 2020-09-30 | 2023-11-21 | 烟台药物研究所 | Compound, and synthetic method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2131192A (en) | 1993-03-04 |
| CN1034864C (en) | 1997-05-14 |
| US5422360A (en) | 1995-06-06 |
| KR930004286A (en) | 1993-03-22 |
| AU649158B2 (en) | 1994-05-12 |
| EP0531812A1 (en) | 1993-03-17 |
| CA2077032A1 (en) | 1993-02-28 |
| TW221689B (en) | 1994-03-11 |
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